Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to a process for the synthesis of 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-carbaldehyde (compound of formula Chem. I below also called compound of formula (I) ), as well as a process for the synthesis of a nitrone of formula Chem. III (also called nitrone or compound of formula (III)) via the synthesis of 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-carbaldehyde according to the invention.
• the modification of the chemical structure of a polymer is particularly sought after when it is desired to bring together a polymer and a filler in a composition.
• This modification generally impacts the chemical and physical properties of the polymer, as well as the properties of the compositions containing it. Consequently, it is always a concern to be able to have new functional polymers which make it possible to improve the reinforcement of a polymer composition comprising a reinforcing filler.
• WO20 15/059269 describes compounds of formula Q-A-B in which the Q group comprises a dipole containing at least one nitrogen atom, A is a divalent group which may or may not be aromatic and B an imidazole ring.
• the compromise between cured rigidity and hysteresis of this rubber composition is improved compared with rubber compositions not comprising any grafted elastomer.
• WO2020/249631 WO2020/249623
• WO2020/249623 thus describes the synthesis of 1-(5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-yl)-N-phenylmethanimine oxide according to the reaction scheme Chem. following SRI:
• This synthetic process thus comprises 5 steps: synthesis and isolation of 5-(hydroxymethyl)furan-2-carbaldehyde (product A) from D-fructose in DMSO; synthesis and isolation of 5-(chloromethyl)furan-2-carbaldehyde (product B) from product A in dichloromethane; synthesis and isolation of 5-((2-methyl-1H-imidazol-1y-1)methyl)furan-2-carbaldehyde (product C) by reaction of product B and 2-methylimidazole in DMF; synthesis and isolation of N-phenylhydroxylamine (product D) from nitrobenzene; and synthesis and isolation of 1-(5-((2-methyl-1H-imidazol-1y-1)methyl)furan-2-yl)-N-phenylmethanimine oxide (product E) from product D in the ethanol.
• Literature data Green Chem., 2011, 13, 1114-1117; Eur. J. Org. Chem. 2011, 1266-1270; Renewable Energy. 2016, 85, 994-1001; ACS Sustainable Chem. Eng. 2019 , 7, 5588-5601; and Angew Chem, Int Ed, 2008, 47, 7924-7926
• a variant of the process according to WO2020/249623 can therefore comprise 4 steps with isolation of each of the reaction intermediates B, C and D in the reaction scheme above.
• polar solvents dimethylformamide (DMF), methyl tert-butyl ether (MTBE), ethanol
• aliphatic alkanes petroleum ether
• aromatic alkanes toluene
• the Applicant has thus developed a new process for the synthesis of a 1,3- dipolar comprising a heteroaromatic ring and an imidazole ring, namely the nitrones of formula (III), in particular the oxide 1-(5-((2-methyl-1H-imidazol-1y-l)methyl)furan- 2-yl)-N-phenylmethanimine of formula (IIa), making it possible to overcome the disadvantages listed above.
• the subject of the invention is a process for the preparation of a compound of formula Chem. I: [Chem. I] comprising the following successive steps:
• step (ii) cooling the mixture from step (i) to give a cooled mixture, separating the cooled mixture into an aqueous phase and an organic phase, and recovering the organic phase, said organic phase comprising the organic solvent and a compound of formula Chem. II:
• the carbohydrate is a monosaccharide, preferably fructose such as D-fructose.
• the organic solvent is toluene.
• the quantity of hydrochloric acid is within a range ranging from 3 to 7 molar equivalents, preferably from 3.5 to 6 molar equivalents, particularly preferably from 4 to 5 molar equivalents relative to the amount of monosaccharide units present in the carbohydrate.
• the quantity of chloride ions provided by the alkali or alkaline-earth metal chloride is within a range ranging from 1.2 to 2.6 molar equivalents, preferably within a range ranging from 1.6 to 2.4 molar equivalents, particularly preferably within a range ranging from 1.7 to 2.2 molar equivalents relative to the amount of monosaccharide units present in the carbohydrate.
• the alkali or alkaline-earth metal chloride is chosen from magnesium chloride and lithium chloride, and is preferably magnesium chloride.
• the phase transfer agent is a quaternary ammonium halide, for example a tetra(C1-C20 alkyl)ammonium halide (e.g. bromide), preferably hexadecyltrimethylammonium bromide, the amount of which is advantageously included in a range ranging from 0.001 to 0.01 molar equivalents with respect to the quantity of monosaccharide units present in the carbohydrate.
• a quaternary ammonium halide for example a tetra(C1-C20 alkyl)ammonium halide (e.g. bromide), preferably hexadecyltrimethylammonium bromide, the amount of which is advantageously included in a range ranging from 0.001 to 0.01 molar equivalents with respect to the quantity of monosaccharide units present in the carbohydrate.
• step (i) comprises the following steps:
• step (ii) addition, preferably in semi-continuous mode, of the composition resulting from step (ii) in the organic solvent heated to a temperature comprised in a range ranging from 35° C. to 90° C., in particular from 45 °C to 80°C, preferably from 55 to 75°C; or includes the following steps:
• composition comprising the organic solvent, hydrochloric acid, alkali or alkaline-earth metal chloride, and optionally the phase transfer agent, said composition being heated to a temperature comprised in a range ranging from from 35°C to 90°C, in particular from 45°C to 80°C, preferably in a range ranging from 55 to 75°C;
• composition comprising the organic solvent, hydrochloric acid, alkali metal or alkaline-earth metal chloride, water, and optionally the phase transfer agent, said composition being heated to a temperature comprised in a range ranging from 35°C to 90°C, in particular from 45°C to 80°C, preferably from 55 to 75°C;
• step (ii) adding the carbohydrate to the heated composition from step (ii); or includes the following steps:
• step (ii) comprises, after the cooling step and before the separation step, a step of filtering the cooled mixture in order to remove the solids present, preferably with a step of washing the solids with organic solvent, preferably with the organic solvent from step (i).
• the amount of 2-methylimidazole during step (iii) is within a range ranging from 2.0 to 3.0, in particular from 2.0 to 2.5, preferably from 2.1 to 2 .2 molar equivalents relative to the amount of the compound of formula Chem. II.
• the mixture obtained during stage (iii) comprising 2-methylimidazole and the organic phase resulting from stage (ii) is maintained at a temperature comprised in a range ranging from 50° C. to 90° C., more preferably 60°C to 80°C, preferably from 65°C to 75°C, preferably for a time comprised within a range ranging from 2 to 8 hours, preferably from 3 to 6 hours.
• step (iii) comprises the following steps:
• step (iiiil) addition preferably in semi-continuous mode, at room temperature, of a fraction of the organic phase resulting from step (ii) to 2-methylimidazole;
• step (iii2) heating the composition from step (iii1) to a temperature within a range ranging from 50 to 90°C, preferably from 60 to 80°C, more preferably from 65°C to 75°C;
• step (iii3) addition, preferably in semi-continuous mode, of the remaining fraction of the organic phase resulting from step (ii) to the heated composition resulting from step (iii2); or includes the next step
• the invention also relates to a process for the preparation of a compound of formula Chem. III: including the following steps:
• step (b) reaction of the compound of formula Chem. I obtained in step (a) with a compound of formula R1-NO 2 in the presence of a reducing agent, preferably zinc, in order to form the compound of formula Chem. III;
• a reducing agent preferably zinc
• R 1 is chosen from the group consisting of linear or branched C1-C20 alkyls; C3-C20 cycloalkyls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; and C6-C20 aryls optionally substituted with one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; preferably R 1 is a C6-C20 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls, more preferably still R 1 is a C6 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls.
• step (b) comprises the following steps:
• step (bl) preparation of a composition comprising the compound of formula Chem. I obtained in step (a), an ammonium salt such as ammonium chloride and a water / ethanol mixture, advantageously with a water / ethanol ratio in mass percentage included in a range from 1/99 to 50 /50, preferably within a range ranging from 5/95 to 30/70, particularly preferably within a range ranging from 7/93 to 15/85;
• step (b2) addition of the compound R1-NO 2 to the composition obtained in step (bl), preferably in an amount comprised in a range ranging from 0.80 to 1.20 molar equivalent, preferably from 0.90 to 1.10 molar equivalent, particularly preferably from 0.95 to 1.05 molar equivalent relative to the quantity of the compound of formula Chem. I; And
• step (b3) addition, preferably in semi-continuous mode, of zinc to the composition obtained in step (b2) maintained at a temperature in a range ranging from 15°C to 25°C, preferably from 15°C to 22 °C, during the addition step.
• the composition resulting from step (b3) is maintained at a temperature in a range ranging from 15° C. to 25° C., preferably from 15° C. to 22° C. for a period comprised in a range ranging from 4 to 6 hours.
• the process according to the invention thus makes it possible to reduce the number of chemical steps compared to the prior art, while using more acceptable solvents from the point of view of toxicity.
• the stages of the process for the synthesis of the nitrones of formula (III) according to the invention are schematized on the reaction diagram Chem. SR2 below from a carbohydrate, D-fructose being preferred: [Chem.
• R 1 is selected from the group consisting of linear or branched C1-C20 alkyls; C3-C20 cycloalkyls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; and C6-C20 aryls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched.
• the number of unit steps is thus reduced to 2 with isolation of only the 5-((2-methyl-1H-imidazol-1y-l)methyl)furan-2-carbaldehyde compounds (compound of formula (I)) and the nitrone of formula (III), by using more acceptable solvents with optimized synthesis yields.
• the use of a two-phase organic phase/aqueous phase medium during the synthesis of the compound of formula (II) limits the generation of decomposition by-products in the reaction medium.
• the method according to the invention can be implemented using carbohydrates other than fructose, such as a polysaccharide such as cellulose or a monosaccharide such as glucose.
• a polysaccharide such as cellulose
• a monosaccharide such as glucose.
• FIG. 1 represents humine (b) formed from a compound of formula (II) prepared in situ in the process according to the invention of example 1 and humine (a) formed from a commercial compound of formula (II) according to Example 2.
• any interval of values designated by the expression "between a and b" represents the range of values going from more than a to less than b (i.e. limits a and b excluded) while any interval of values denoted by the expression "from a to b” signifies the domain of values ranging from a to b (i.e. including the strict limits a and b).
• the compounds mentioned in the description can be of fossil origin or biosourced. In the latter case, they can be, partially or totally, derived from biomass or obtained from renewable raw materials derived from biomass. Obviously, the compounds mentioned can also come from the recycling of materials already used, that is to say they can be, partially or totally, from a recycling process, or even obtained from raw materials themselves. even from a recycling process. This concerns in particular polymers, plasticizers, fillers, etc.
• hexose saccharide with 6 carbon atoms
• aldohexose saccharide bearing an aldehyde function in the terminal position, that is to say on carbon atom 1
• ketohexose saccharide bearing a ketone function on carbon atom 2.
• allose altrose, glucose, mannose, gulose, idose, galactose, talose, fructose, allulose, gululose or galactulose, in the form D or L.
• the monosaccharide will preferably be in a cyclized form.
• polysaccharide is meant, within the meaning of the present invention, a molecule comprising at least two monosaccharide molecules as defined above (called monosaccharide units) linked together by a covalent bond. It could be cellulose.
• C1-Cx alkyl is meant, within the meaning of the present invention, a saturated hydrocarbon chain, linear or branched, comprising 1 to x carbon atoms.
• a saturated hydrocarbon chain linear or branched, comprising 1 to x carbon atoms.
• C3-C20 cycloalkyl is meant, within the meaning of the present invention, a saturated hydrocarbon ring, comprising 3 to 20 carbon atoms.
• a saturated hydrocarbon ring comprising 3 to 20 carbon atoms.
• aliphatic hydrocarbon chain is meant within the meaning of the present invention, a saturated or unsaturated, linear or branched hydrocarbon chain, optionally comprising one or more non-aromatic hydrocarbon rings.
• it is a saturated, linear or branched hydrocarbon chain, namely an alkyl chain.
• C6-C20 aryl is meant, within the meaning of the present invention, an aromatic hydrocarbon-based group comprising from 6 to 20 carbon atoms, and comprising one or more adjoining rings, such as for example a phenyl or naphthyl group.
• it is phenyl.
• ambient temperature is meant, within the meaning of the present invention, a temperature comprised in a range ranging from 15° C. to 40° C., preferably from 20° C. to 25° C., more preferably still a temperature of 23° C. .
• a first object of the invention relates to a process for the preparation of the compound of formula (I), also called Chem. I:
• step (ii) cooling the mixture from step (i) to give a cooled mixture, separating the cooled mixture into an aqueous phase and an organic phase, and recovering the organic phase, said organic phase comprising the organic solvent and a compound of formula (II), also called Chem. II:
• the compound of formula (I) is 5-((2-methyl-1H-imidazol-1y-1)methyl)furan-2-carbaldehyde.
• the compound of formula (II) is 5-(chloromethyl)furan-2-carbaldehyde.
• the compound of formula (II) is obtained from a mixture comprising a carbohydrate, an alkali or alkaline-earth metal chloride, hydrochloric acid, water, an organic solvent which is an aprotic polar solvent insoluble in water and optionally a phase transfer agent, said mixture being heated to a temperature within a range from 35°C to 90°C, preferably within a range from 45°C at 80°C, in a particularly preferred manner comprised within a range going from 55°C to 75°C and said carbohydrate being a monosaccharide, a polysaccharide or a mixture thereof.
• the carbohydrate When the carbohydrate is a polysaccharide, it will first be hydrolyzed into monosaccharides in the acid medium (hydrochloric acid) of step (i).
• the monosaccharide is then converted into a compound of formula (II) in the presence of the alkali or alkaline-earth metal chloride in the acid medium of step (i).
• the carbohydrate can be a polysaccharide such as inulin, cellulose or hemicellulose.
• the polysaccharide is cellulose.
• the carbohydrate can be a monosaccharide such as fructose, sorbose or glucose.
• the monosaccharide is fructose such as D-fructose.
• the carbohydrate is fructose or cellulose.
• the carbohydrate such as fructose is a biobased carbohydrate.
• biobased carbohydrate is meant within the meaning of the present invention a carbohydrate derived from biomass which can be differentiated from the carbohydrate synthesized from fossil raw materials by the methods described in standard ASTM D6866-12.
• the organic solvent is an aprotic polar solvent that is not soluble in water, i.e. the mixture of the organic solvent and water is two-phase. It can be toluene, an aryl halide (e.g. chlorobenzene) or a ketone such as a di((Ci-Ce)alkyl)-ketone (e.g. methyl isobutyl ketone).
• the organic solvent is toluene.
• toluene as organic solvent in step (i) is particularly preferred because the applicant has unexpectedly observed that the reaction to obtain the compound of formula (I) in toluene leads to the generation of humin of a different structure than humin formed using solvents other than toluene (such as DMF and isopropanol).
• This humin is less sticky than that formed in the other solvents: it is thus more easily eliminated during the downstream purification operations of the compound of formula (I).
• the less sticky nature of the humin limits the fouling of equipment and their cleaning is made easier.
• Toluene is also a more acceptable alternative to prior art solvents.
• the temperature of the mixture comprising a carbohydrate, an alkali or alkaline earth metal chloride, hydrochloric acid, water, an organic solvent which is an aprotic polar solvent insoluble in water and optionally a transfer agent phase is chosen so as to maximize yield and limit parasitic chemistry. Too high a temperature can lead to rapid degradation of the compound of formula (II) formed, decline in selectivity and yield. Too low a temperature (below 30° C.) can lead to a low yield of compound of formula (II).
• the temperature of the mixture can thus be within a range ranging from 35°C to 90°C, preferably from 45°C to 80°C, particularly preferably from 55°C to 75°C.
• the amount of hydrochloric acid is advantageously within a range ranging from 3 to 7 molar equivalents, preferably from 3.5 to 6 molar equivalents, particularly preferably from 4 to 5 molar equivalents relative to the amount of monosaccharide units present in the carbohydrate.
• the amount of chloride ions provided by the alkali or alkaline-earth metal chloride is advantageously within a range ranging from 1.2 to 2.6 molar equivalents, preferably within a range ranging from 1.6 to 2.4 equivalents molar, particularly preferably in a range ranging from 1.7 to 2.2 molar equivalents with respect to the quantity of monosaccharide units present in the carbohydrate.
• the alkali or alkaline-earth metal chloride is chosen from magnesium chloride and lithium chloride, and is preferably magnesium chloride.
• Magnesium chloride can be hydrated, in particular hexahydrate.
• the amount of magnesium chloride is advantageously within a range ranging from 0.6 to 1.3 molar equivalents, preferably within a range ranging from 0.8 to 1.2 molar equivalents, particularly preferably in a range ranging from 0.85 to 1.1 molar equivalents with respect to the quantity of monosaccharide units present in the carbohydrate.
• the amount of lithium chloride is advantageously within a range ranging from 1.2 to 2.6 molar equivalents, preferably within a range ranging from 1.6 to 2.4 molar equivalents, particularly preferably in a range ranging from 1.7 to 2.2 molar equivalents with respect to the quantity of monosaccharide units present in the carbohydrate.
• step (i) can comprise a phase transfer agent.
• a phase transfer agent can make it possible to improve the yield of the reaction for obtaining the compound of formula (II).
• the phase transfer agent is advantageously a quaternary ammonium halide, for example a tetra(C1-C20 alkyl)ammonium halide (eg bromide), and preferably hexadecyltrimethylammonium bromide, the amount of which is advantageously within a range from 0.001 to 0.01 molar equivalents relative to the amount of units monosaccharides present in the carbohydrate.
• the mixture of carbohydrate, an alkali or alkaline-earth metal chloride, hydrochloric acid, water, organic solvent and optionally a phase transfer agent is preferably obtained according to a semi-continuous mode, c that is to say by proceeding with the addition in semi-continuous mode, as defined above, of a part of the components of the mixture on the other part of the components of the mixture.
• a composition comprising the carbohydrate, the alkali or alkaline-earth metal chloride, the hydrochloric acid, the water, and optionally the phase transfer agent can be added semi-continuously in the organic solvent.
• the addition is advantageously carried out in semi-continuous mode to limit the concentration of the carbohydrate in the organic phase and consequently the parasitic reactions.
• the composition comprising the carbohydrate, the alkali or alkaline-earth metal chloride, hydrochloric acid, water, and optionally the phase transfer agent can be prepared by adding the carbohydrate, preferably at room temperature, to a mixture comprising the alkali metal or alkaline-earth metal chloride, the hydrochloric acid and optionally the phase transfer agent.
• the carbohydrate can also be added alone or in solution in water to a mixture containing the other reactants.
• the components of the composition can be added to the carbohydrate.
• a mixture comprising the alkali metal or alkaline-earth metal chloride, hydrochloric acid and optionally the phase transfer agent can also be added to a solution of organic solvent and carbohydrate.
• a hydrochloric acid solution can also be added to a mixture comprising the carbohydrate, the organic solvent, the alkali or alkaline-earth metal chloride, the water, and optionally the phase transfer agent.
• step (i) of the method comprises the following steps:
• step (ii) addition, preferably in semi-continuous mode, of the composition resulting from step (ii) in the organic solvent heated to a temperature comprised within a range ranging from 35°C to 90°C, in particular from 45°C to 80°C, preferably from 55 to 75°C.
• step (i) of the method comprises the following steps:
• step (i) of the method comprises the following steps:
• composition comprising the organic solvent, hydrochloric acid, alkali or alkaline-earth metal chloride, and optionally the phase transfer agent, said composition being heated to a temperature comprised in a range ranging from from 35°C to 90°C, in particular from 45°C to 80°C, preferably from 55 to 75°C;
• step (i) of the method comprises the following steps:
• composition comprising the organic solvent, hydrochloric acid, alkali metal or alkaline-earth metal chloride, water, and optionally the phase transfer agent, said composition being heated to a temperature comprised in a range ranging from 35°C to 90°C, in particular from 45°C to 80°C, preferably from 55 to 75°C;
• step (i) of the method comprises the following steps:
• step (i) is also adapted according to the nature of the carbohydrate.
• the duration of step (i) is adapted so as to also optimize the prior step of hydrolysis of the polysaccharide into monosaccharide.
• step (i) is typically less than 90 minutes.
• the mixture is stirred with a stirring speed making it possible to ensure good mixing of the components while limiting the shear.
• the stirring speed is within a range from 300 to 1000 rpm.
• Step (ii) makes it possible to recover the organic phase containing the compound of formula (II) formed in step (i), without however isolating this compound.
• the compound of formula (II) mainly partitions in the organic phase of the mixture based on the organic solvent, namely an aprotic polar solvent which is not soluble in water such as toluene.
• step (i) the mixture resulting from step (i) is cooled, ideally to ambient temperature, before separating it into an organic phase and an aqueous phase, and recovering the organic phase which contains the compound of formula (II).
• a filtration step is carried out after the cooling step and before the separation step in order to eliminate the solid matter present.
• the solids are advantageously washed with the organic solvent of the previous step, namely an aprotic polar solvent which is not soluble in water such as toluene.
• These solid materials also called humin, consist mainly of oligomers of monosaccharide units and/or furan derivatives.
• the organic phase is then advantageously treated by implementing steps well known to those skilled in the art.
• the organic phase is washed, one or more times, with a saturated aqueous NaCl solution.
• the organic phase can optionally be dried, for example by bringing it into contact with MgSCh, by azeotropic distillation or by passage over a membrane/cartridge drying rack or on a sieve.
• the compound of formula (II) mainly partitions in the organic phase and is not isolated before engaging in step (iii), which constitutes an improvement of the existing process which required additional and tedious steps of separation and purification.
• step (ii) is stable if it is stored at low temperature (typically in a range ranging from ⁇ 20° C. to +4° C.) for at least 3 days and for several hours at 70°C.
• low temperature typically in a range ranging from ⁇ 20° C. to +4° C.
• the isolated compound of formula (II) is not very stable without a stabilizing agent and decomposes rapidly at room temperature: it must therefore be stored cold (-5°C) and in the presence of additives.
• the compound of formula (II) is obtained with a yield greater than 30%, in particular greater than 50%, preferably greater than 60%.
• Step (iii) of synthesis of the compound of formula (I) from the compound of formula (II) is carried out in the same organic solvent, namely an aprotic polar solvent which is not soluble in water such as toluene, which that of step (i), the latter being present in the organic phase recovered in step (ii) and containing the compound of formula (II).
• an aprotic polar solvent which is not soluble in water such as toluene
• WO2020/249631 describes the synthesis of the compound of formula (I) from compound (II) in DMF which has the disadvantage of having a certain toxicity.
• Patent US4729851 also describes the synthesis of a molecule close to the compound of formula (I) with the difference that it comprises an imidazole and not a methylimidazole.
• the preparation of this compound is carried out in chloroform, which is less acceptable from an HSE point of view than the organic solvent, namely an aprotic polar solvent which is not soluble in water, in particular toluene, used in step (iii) .
• step (iii) of the same organic solvent namely an aprotic polar solvent insoluble in water such as toluene
• step (i) also allows the direct implementation of the organic phase comprising the organic solvent and the compound of formula (II) resulting from stage (ii) and thus avoiding the stages of separation and purification of the compound of formula (II).
• the compound of formula (I) is obtained by reacting 2-methylimidazole and the compound of formula (II) present in the organic phase resulting from step (ii), the 2-methylimidazole being in molar excess relative to the compound of formula (II).
• the amount of 2-methylimidazole during step (iii) is within a range ranging from 2.0 to 3.0 molar equivalents, preferably within a range ranging from 2.0 to 2, 5, more preferably from 2.1 to 2.2 molar equivalents relative to the amount of the compound of formula (II).
• the amount of 2-methylimidazole to be used during step (iii) will be more particularly calculated from the concentration of compound of formula (II) in the organic phase resulting from step (ii) determined by a dosage, by example by NMR.
• the mixture of 2-methylimidazole and the organic phase containing the non-isolated compound of formula (II) resulting from step (ii) is preferably carried out in semi-continuous mode.
• 2-Methylmidazole is added in semi-continuous mode to said organic phase or else said organic phase is added in semi-continuous mode to 2-methylmidazole.
• step (iii) comprises the following steps:
• step (iii2) heating of the composition resulting from step (iiiil) to a temperature comprised in a range ranging from 50 to 90° C., preferably from 60° C. to 80° C., more preferably from 65° C. to 75° C. VS; And
• step (iii3) addition, preferably in semi-continuous mode, of the remaining fraction of the organic phase resulting from step (ii) to the heated composition resulting from step (iii2).
• step (iii) comprises the following step:
• the 2-methylimidazole can be added in the form of a composition comprising 2-methylimidazole and a non-nucleophilic polar solvent.
• the non-nucleophilic polar solvent can be an alcoholic solvent such as isopropanol.
• the semi-continuous addition time according to any one of the preceding embodiments is advantageously within a range ranging from 2 hours to 8 hours, preferably from 3 hours to 6 hours.
• the mixture obtained during step (iii) comprising 2-methylimidazole and the organic phase resulting from step (ii) is maintained at a temperature comprised in a range ranging from 50° C. to 90° C., more preferentially from 60° C. to 80° C., more preferentially from 65° C. to 75° C., preferably for a time comprised in a range ranging from 4 to 6 hours, in particular from the end of the addition, in particular in semi- continuously, 2-methylimidazole or the organic phase from step (ii).
• the use of a commercial compound of formula (II) such as that of ABCR leads to a yield of compound (I) three times lower under the same operating conditions.
• the compounds of formula (II) available commercially contain impurities, in particular acetic acid, which differ from those of the compound of formula (II) prepared in situ in the process according to the invention. These impurities show that the synthesis routes are different. In addition, these seem to have a negative impact on yield, with the formation of humin in greater quantities. It is indeed known that acid impurities such as Bronsted acids can have an impact on the yield of adduct and the formation of polymeric by-products as described in US4729851A.
• the humine formed during step (iii) from a compound of formula (II) prepared in-situ in the process according to the invention has a less clogging character than the humine formed from a commercial compound of formula (II).
• Figure 1 comparing the humin (b) formed from a compound of formula (II) prepared in-situ in the process according to the invention of example 1 and the humin (a) formed from a compound of commercial formula (II) according to Example 2.
• Steps (i) to (iii) are therefore interdependent and must all be implemented to ensure maximum yield, with gains in unit steps and to avoid the presence of impurities present in the commercial compounds of formula (II). which negatively affect performance.
• step (iii) part of the compound of formula (I) is trapped in the solid precipitate which forms during the reaction.
• the compound of formula (I) present in this precipitate can be recovered by techniques well known to those skilled in the art, such as for example by filtration of the mixture resulting from step (iii) and successive washings of the residue from the filtration (commonly called cake) with the organic solvent, namely a water-insoluble polar aprotic solvent such as toluene, from step (i), to maximize the recovery of this compound of formula (I) in the filtrate .
• the compound of formula (I) can then be separated from the filtrate by techniques well known to those skilled in the art, such as by crystallization. If the purity is insufficient, additional purification operations are possible, such as liquid-liquid extractions of the organic solvent/water type.
• the dichloromethane/water pair for the liquid/liquid extraction is particularly preferred.
• the compound of formula (I) is recovered with a yield greater than 30%, preferably greater than 40%. It is obtained with a molar purity greater than 90%.
• step (b) reaction of the compound of formula (I) obtained in step (a) with a compound of formula R 1 - NO 2 in the presence of a reducing agent, preferably zinc, in order to form the compound of formula (III );
• a reducing agent preferably zinc
• R 1 is chosen from the group consisting of linear or branched C1-C20 alkyls; C3-C20 cycloalkyls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; and C6-C20 aryls optionally substituted with one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; preferably R 1 is a C6-C20 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls, more preferably still R 1 is a C6 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls.
• R 1 is a C6-C20 aryl optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched, are preferred; preferably R 1 is a C6-C20 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls, preferably R 1 is a C6 aryl optionally substituted by one or more alkyls C1-C6, preferably one or more C1-C3 alkyls. Even more preferentially, among the compounds of formulas (III), the compounds of formulas (IIIa) and (IIIb) are the preferred ones.
• the compound of formula (Ilia), also called Chem. Ilia is 1-(5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-yl)-N-phenyl Imethanimine oxide.
• Said step (b) of the process according to the invention is advantageously carried out in the presence of a reducing agent.
• the reducing agent is chosen from zinc and hydrogen, preferably is zinc.
• the quantity of reducing agent is from 1.5 to 6 molar equivalents, preferably from 2 to 5 molar equivalents, relative to the quantity of compound of formula (I).
• step (b) will advantageously also be carried out in the presence of a metallic hydrogenation catalyst known to those skilled in the art, whether it is supported (such as for example Pd/C , Pt/C, Ru/C or Rh/C) or unsupported (such as Tebbe's reagent or Raney's nickel).
• a metallic hydrogenation catalyst known to those skilled in the art, whether it is supported (such as for example Pd/C , Pt/C, Ru/C or Rh/C) or unsupported (such as Tebbe's reagent or Raney's nickel).
• step (b) When the reducing agent is zinc, step (b) will advantageously be carried out in the presence of an acid, advantageously chosen from an organic acid (e.g. acetic acid, propionic acid, or any alkylated organic carboxylic acid) and a salt of weak acid (e.g. an ammonium salt such as ammonium chloride).
• an acid advantageously chosen from an organic acid (e.g. acetic acid, propionic acid, or any alkylated organic carboxylic acid) and a salt of weak acid (e.g. an ammonium salt such as ammonium chloride).
• an ammonium salt such as ammonium chloride.
• Said step (b) is also advantageously carried out in the presence of a solvent.
• the solvent is chosen from water, an alcohol solvent (e.g. ethanol, isopropyl alcohol), an ether solvent (e.g. tetrahydrofuran, dioxane), a nitrile solvent (acetonitrile, etc.) and mixtures thereof; preferably chosen from water, an alcohol solvent, and mixtures thereof.
• an alcohol solvent e.g. ethanol, isopropyl alcohol
• an ether solvent e.g. tetrahydrofuran, dioxane
• a nitrile solvent acetonitrile, etc.
• mixtures thereof preferably chosen from water, an alcohol solvent, and mixtures thereof.
• the mixture is advantageously single-phase.
• the mixture of solvents is advantageously a water/alcohol solvent mixture such as a water/ethanol mixture.
• the solvent is a water/ethanol mixture, advantageously with a water/ethanol ratio in mass percentage included in a range ranging from 1/99 to 50/50, preferably included in a range ranging from from 5/95 to 30/70, particularly preferably in a range extending from 7/93 to 15/85.
• the water/ethanol mixture is acceptable from an HSE point of view and allows for maximized performance.
• the compound of formula R1-NO 2 used in step (b) is a compound in which R 1 is chosen from the group consisting of linear or branched C1-C20 alkyls; C3-C20 cycloalkyls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched; and C6-C20 aryls optionally substituted by one or more aliphatic hydrocarbon chains, preferably saturated and linear or branched.
• the compound of formula R1-NO 2 used in step (b) is a compound in wherein R 1 is C6-C20 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls.
• the compound of formula R1-NO 2 used in step (b) is a compound in which R 1 is a C6 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more alkyls in C1-C3.
• step (b) comprises the following steps:
• step (b2) addition of the compound of formula R1-NO 2 , with R 1 as defined above, to the composition obtained in step (bl), preferably in an amount comprised in a range from 0.80 to 1 .20 molar equivalent relative to the amount of the compound of formula (I), preferably from 0.90 to 1.10, particularly preferably from 0.95 to 1.05;
• step (b3) addition, preferably in semi-continuous mode, of zinc to the composition obtained in step (b2) maintained at a temperature within a range from 15°C to 25°C, preferably 15°C at 22°C, during the addition step.
• step (bl) a solution of ammonium salt in water is added to a solution of the compound of formula (I) in ethanol.
• the addition of the components is preferably carried out in the following order: to the water/ethanol mixture comprising the compound of formula (I) and the ammonium salt is added the compound of formula R 1 -NChthen zinc, preferably in semi-continuous mode.
• Step (b3) is advantageously carried out at a controlled temperature comprised in a range ranging from 15°C to 25°C, preferably from 15°C to 22°C, preferably around 20°C, in order to limit the formation of by-products.
• the composition resulting from step (b3), before carrying out step (c), is maintained at a temperature comprised in a range ranging from 15° C. to 25° C., preferentially from 15 to 22° C., preferably for 4 to 6 hours from the end of the addition, preferably in semi-continuous mode, of the zinc.
• a stoichiometric amount of compound of formula R1-NO 2 relative to the compound of formula (I) is used. An excess of compound R1-NO 2 would not make it possible to improve the yield of compound of formula (I) and would, moreover, generate by-products.
• step (c) the compound of formula (III) is recovered, in particular after conventional treatment and purification steps for those skilled in the art.
• the medium is filtered then the residue is washed with ethanol; the filtrates are combined and evaporated; the residue is taken up in an MTBE/ethyl acetate mixture, then recrystallized at ambient temperature.
• the compound of formula (III) is obtained with a yield greater than 70% relative to the initial quantity of compound of formula (I).
• the compound of formula (III) is advantageously obtained with a molar purity greater than 90 mol%.
• polymer modified by grafting or “polymer modified by grafting”, is meant a polymer obtained by grafting reaction of the compound of formula (III) whose nitrone function is capable of forming a covalent bond with an unsaturation of the chain of the polymer.
• a polymer generally comprises at least one main polymer chain.
• This polymer chain can be qualified as main from the moment all the other chains of the polymer are considered as pendant chains as mentioned in the document "Glossary of basic terms in polymer science” (IUPAC recommendations 1996), PAC, 1996, 68 , 2287, p2294.
• “unsaturation” is meant a multiple covalent bond between two carbon atoms, this multiple covalent bond possibly being a carbon-carbon double bond or a carbon-carbon triple bond, preferably a carbon-carbon double bond.
• initial polymer chain is meant within the meaning of the present invention the chain of the polymer before the grafting reaction, this chain comprising at least one unsaturation capable of reacting with the compound of formula (III).
• the initial polymer is therefore the polymer serving as starting reagent during the grafting reaction.
• the grafting reaction makes it possible from an initial polymer to obtain a modified polymer.
• this initial polymer is an elastomer, that is to say a polymer having elastic properties, more preferably still a diene elastomer.
• diene elastomer or indistinctly rubber is meant an elastomer consisting at least in part (i.e., a homopolymer or a copolymer) of repeating units derived from diene monomers, that is to say from monomers carrying two carbon-carbon double bonds, conjugated or not.
• the diene elastomer can be natural or synthetic.
• the compound of formula (III), more preferably the compound of formula (III) in which R 1 is a C6 aryl optionally substituted by one or more C1-C6 alkyls, preferably one or more C1-C3 alkyls, plus preferentially the compounds of formula (IIIa) and (IIIb), is useful as agent for modifying a polymer. It can be grafted onto one or more polymers comprising at least one unsaturated carbon-carbon bond, in particular this polymer can be an elastomer and more particularly a diene elastomer as defined previously.
• the polymer then carries along the main polymer chain one or more pendent groups resulting from the grafting reaction of the compound of formula (III).
• these pendant groups are randomly distributed along the main polymer chain.
• the molar degree of grafting of the compound of formula (III) is within a range ranging from 0.01% to 15%, preferably from 0.05% to 10%, more preferably from 0, 07 to 5%.
• molar rate of grafting is meant the number of moles of compound of formula (III) grafted onto the polymer per 100 moles of repeating unit constituting the initial polymer.
• the molar rate of grafting can be determined by conventional methods of polymer analysis, such as for example NMR analysis.
• the modified polymer is obtained according to a process comprising a step of grafting onto an initial polymer comprising at least one unsaturation of the compound of formula (III) by cycloaddition [3+2] of the nitrone unit of the compound of formula (III) on said unsaturation.
• the grafting of the compound of formula (III) can be carried out in bulk, for example in an extruder, an internal mixer or in a mixer external such as a roller mixer.
• the process for preparing a modified polymer can be carried out in solution, for example continuously or discontinuously.
• the polymer thus obtained by grafting can be separated from its solution by any type of means known to those skilled in the art and in particular by a steam stripping operation.
• the initial polymer is an elastomer, more preferably still is a diene elastomer.
• the modified polymer obtained by grafting the compound of formula (III) as defined above can be used in a composition further comprising at least one additive.
• the additives that can be used in the composition can be plasticizers (such as plasticizing oils and/or plasticizing resins), fillers (reinforcing or non-reinforcing), pigments, protective agents (such as anti-ozone waxes, chemical anti-ozonants, antioxidants and anti-fatigue agents), reinforcing resins (as described for example in application WO 02/10269), a crosslinking system, for example based on sulfur and other vulcanization, and/or peroxide and/or bismaleimide.
• this additive is a reinforcing filler, more preferably this additive is an inorganic reinforcing filler, even more preferably this additive is a silica.
• the conversion, the yield of measured product, the structural analysis as well as the determination of the molar purities of the synthetic molecules are carried out by an NMR analysis.
• the spectra are acquired on an Avance 3400 MHz BRUKER spectrometer equipped with a 5 mm BBFO-zgrad "broadband" probe.
• the quantitative 1 H NMR experiment uses a simple 30° pulse sequence and a repetition delay of 3 seconds between each of the 64 acquisitions.
• the samples are solubilized in a deuterated solvent, deuterated dimethyl sulfoxide (DMSO) unless otherwise indicated.
• DMSO deuterated dimethyl sulfoxide
• the deuterated solvent is also used for the lock signal.
• the calibration is carried out on the proton signal of deuterated DMSO at 2.44 ppm compared to a TMS reference at 0 ppm.
• the 1 H NMR spectrum coupled with the 2D HSQC 1 H/ 13 C and HMBC 1 H/ 13 C experiments allow the structural determination of the molecules (cf. attribution tables).
• the molar quantifications are carried out from the quantitative 1 D 1 H NMR spectrum.
• concentration and therefore the yield of compound (II) in solution is obtained by the same technique, by external calibration by adding a known quantity of a product whose signals do not interfere with the signals of the species present, such as for example the benzyl benzoate.
• the example below is a preferred embodiment of the invention. Other embodiments are possible.
• the compound of formula (I) is synthesized according to steps (i) to (iv) of the process according to the invention from D-fructose.
• D-fructose is purchased from Aldrich under the reference F0127.
• Toluene (1040 g, i.e. 5.8 kg/kg of D-fructose) is introduced into a 500 ml reactor in order to obtain a solution called Sol. B.
• the Sol solution is heated to 70° C. and stirred at 700 rpm.
• B. The Sol solution.
• A is added drop by drop to the Sol solution. B for a period of 20 min.
• the reaction mixture is then maintained at a temperature of 70° C. for 20 minutes. The formation of a black powder is observed in the medium.
• reaction is monitored by thin layer chromatography (TLC) using a 90/10 (vol/vol) CfLCL/McOH mixture as elution solvent.
• TLC thin layer chromatography
• the revelation is carried out with an iodine/silica mixture.
• reaction mixture from step (i) is filtered on a Büchner funnel under vacuum.
• the solid (black powder) is washed with toluene three times.
• the mass of toluene added to each rinse is approximately 5% by mass of the total reaction volume, i.e. 100 g, then the solid is removed.
• the biphasic filtrate composed of an upper organic phase of brown/red color (34% v/v) and a lower aqueous phase of yellow color (66% v/v) is recovered. After decantation and separation, the upper organic phase is recovered. The aqueous phase is not preserved.
• the organic phase is washed with brine (concentration of NaCl ⁇ 37% by mass in distilled water) until the aqueous phase has a pH greater than or equal to 1, from preferably greater than or equal to 5.
• brine concentration of NaCl ⁇ 37% by mass in distilled water
• a person skilled in the art will know how to adapt the number of washings/extraction of the organic phase according to the size of the reactor (cf. Table 1).
• the solutions are allowed to settle after each wash.
• the Sol reaction mixture. D is left to settle while maintaining the temperature at 70° C.; then the yellow clear supernatant phase is recovered, for example by aspiration.
• the residual black deposit in the reactor is washed 3 times with toluene, leaving 30 minutes under stirring at 70° C. each time.
• the mass of toluene added for each wash corresponds to about 40% to 50% of the mass of the complete reaction medium (Sol. D), ie 450 g of toluene.
• the supernatants are recovered each time after decantation.
• the organic phases that is to say the initial supernatant phase and the organic phases resulting from the washings with toluene
• the solution is filtered to recover crystals of yellow/orange or white color on the one hand and the filtrate on the other hand.
• the filtrate is put at -20° C.
• the black deposit from step (iv) is a finely divided solid, like a powder (see Figure 1(b)).
• the compound of formula (I) synthesized from the compound of formula (II) not isolated from step (ii) is obtained with a yield of 46% (60 g), with a molar purity greater than 90%, determined by 1 H NMR in CDCL.
• the peaks of the 1 H and 13 C NMR spectra are detailed in Table 2 below with the numbering of the carbon atoms presented on the Chem formula. I-NMR.
• Steps (iii) and (iv) were then carried out under the same conditions described in example 1 above, by adapting the quantities of reagents and solvents introduced, while maintaining the same molar and/or mass ratios according to the case.
• the black deposit obtained in Tissue from step (iv) is a pasty solid (see Figure 1(a)). This impurity is more difficult to remove than the black powdery deposit obtained with the process of the invention.
• step (iv) the yield of the compound of formula (I) obtained from the compound of formula (II) marketed is 14% (2.1 g), with a molar purity equal to 80%, determined by 1 H NMR in CDCL.
• the peaks of the 1 H and 13 C NMR spectra are detailed in Table 3 below with the numbering of the carbon atoms presented on the Chem formula. I-NMR.
• D-fructose is purchased from Aldrich under the reference F0127.
• Steps (i) to (iv) of Example 1 are carried out identically and the compound of formula (I) is obtained with a yield of 46% (60 g) and a molar purity greater than 90%, determined by 1 H NMR in CDCL.
• the peaks of the 1 H and 13 C NMR spectra are detailed in Table 5 below with the numbering of the carbon atoms presented on the Chem formula. I-NMR.
• Ammonium chloride (15 g, ie 1.1 equiv. with respect to the compound of formula (I)) is dissolved in a foot of water to obtain a solution called Sol. F.
• the Sol solution .F is poured onto the Sol solution. E at room temperature and with stirring.
• nitrobenzene 32 g, 1 equiv. relative to the compound of formula (I)
• the mixture is left to stir for 10 minutes at room temperature, then the medium is cooled to a temperature of 18° C. with stirring.
• the zinc 52 g, i.e. 3 equiv.
• reaction medium is stirred at 850 rpm for 4.5 hours.
• the revelation is carried out under a UV lamp at a wavelength of 254 nm or by NMR (disappearance of the aldehyde signal at 9.7 ppm).
• step (b) The solution obtained at the end of step (b) is filtered through a Büchner funnel, quality filter 391; 0.15mm thick; retention of particles 2 to 3 ⁇ mm, “SartoriusTM”) in order to eliminate zinc.
• the solid, consisting mainly of zinc, is washed twice with ethanol (120 g), the mass of ethanol involved in each wash corresponds to approximately 30% of the total mass of the reaction medium of step (b) .
• the yellow/orange colored filtrates, which still contain a yellow/white precipitate, are combined.
• the combined filtrates are filtered a second time.
• a precipitate (zinc complexed with the compound of formula (Ilia)) and/or with the compound of formula (I) and reaction by-products, can form in the filtrate.
• This precipitate is soluble in dimethylsulfoxide.
• the volatile compounds are separated by placing the filtrate in distillation equipment, such as a rotary evaporator, by limiting the heating to prevent the degradation of the compound of formula (Ilia) (Temperature of the boiler ⁇ 60° C., the distillation time is about 1 hour).
• the crude compound of formula (IIIa) is obtained in the form of a brown/orange solid.
• the yield of compound of formula (Ilia) obtained from the compound of formula (I) at this stage is 80%, ie 80 g.
• the crude compound of formula (Ilia) is crystallized at 25° C. from an MTBE (Methyl tert-butyl ether)/ethyl acetate (67/33 vol/vol, i.e.
• Example 4 Obtaining the compound of formula (Ilia) according to a process not in accordance with the invention (process in 5 stages with isolation of the 4 intermediate products of synthesis)
• Example 5 synthesis of the compound of formula (Ilia) according to a process not in accordance with the invention (Process in 4 stages with isolation of the 3 intermediate products of synthesis)
• Table 9 compares the number of steps, the number of intermediate synthesis products that were isolated, the overall yield of the process and the nature of the solvent as well as their quantity for each example.
• Example 3 the solvents, the amounts of solvent and the yields indicated in Table 9 are taken from the experimental data above.
• the reaction medium is diluted with l water (50 ml) then the organic phase is separated.
• the aqueous phase is extracted 4 times with dichloromethane (4 times 20 ml). Phase fractions are combined then washed with water (4 times 5 ml) then concentrated under reduced pressure (2-3 mbar; 32°C) to yield a black oil (2.44 g; 12.8 mmol) with a yield of 55%.
• This product proceeds to the next step without further purification.
• the reaction flask is cooled with ice water and in one hour gradually in small portions, with good stirring, 15 g of zinc powder are added keeping the temperature constantly between 14°C and 16°C. Once the addition of the zinc powder is complete, the mixture is allowed to stand at room temperature with constant stirring for an additional 10 minutes.
• the reaction solution is filtered in order to separate it from the zinc oxide. The first filtrate is recovered separated by pouring it into a beaker. The zinc oxide in the funnel collected by filtration is carefully washed with 200 ml of water at 40° C. and the second filtrate is separated by pouring it into a second beaker.
• the two filtered solutions are cooled separately in ice water and saturated with stirring with finely powdered sodium chloride.
• the amount of sodium chloride for the first solution is about 45 g and for the second solution about 60 g.
• the colorless crystals of crude phenylhydroxylamine deposited are filtered off and, without washing, are dried under vacuum.
• the crude phenylhydroxylamine is purified by crystallization from a product giving benzene, which melts at 81°C.
• Example 3 requires fewer different organic solvents (2 versus 6) and a lower total quantity of organic solvents than the route of Example 4 (92.1 kg versus 200 kg).
• the route according to the invention is also intended to be more productive: the concentration of the species is higher, the reaction times are reduced, the yield is improved. The total yield is also improved.
• example 5 compared to the synthesis process of the invention, makes it possible to obtain the product of formula (IIa) with the same overall reaction yield.
• toxic organic solvents e.g. dichloroethane
• the number of different organic solvents is higher (7 versus 2) than for the synthesis process according to the invention, as well as the total quantity of organic solvents (1549.2 kg versus 200 kg).
• the compound of formula (I) is synthesized according to steps (i) to (iv) of the process according to the invention from D-fructose (see Example 1).
• Step (b) condensation reaction between 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-carbaldehyde (compound of formula (i)) and N-p-Tolyl)hydroxylamine to obtain 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-yl)-N-tolylmethanimine oxide (compound of formula (IIIb))
• E. Ammonium chloride (15 g, ie 1.1 equiv. with respect to the compound of formula (I)) is dissolved in a foot of water to obtain a solution called Sol. F.
• the Sol solution. F is cast on the Sol solution. E at room temperature and with stirring.
• 4-nitrotoluene 36 g, 1 equiv. relative to the compound of formula (I) is added to the reaction medium with stirring, at ambient temperature.
• the mixture is left to stir for 10 minutes at room temperature, then the medium is cooled to a temperature of 18° C. with stirring.
• the zinc 52 g, or 3 equiv. relative to the compound of formula (I)
• the reaction medium is stirred at 850 rpm for 4.5 hours.
• the revelation is carried out under a UV lamp at a wavelength of 254 nm or by NMR (disappearance of the aldehyde signal at 9.7 ppm).
• Step (c) recovery and purification of 5-((2-methyl-1H-imidazol-1-yl)methyl)furan-2-yl)-N-tolylmethanimine oxide (compound (IIIb))
• step (b) The solution obtained at the end of step (b) is filtered through a Büchner funnel, quality filter 391; 0.15mm thick; retention of particles 2 to 3 iimm, “SartoriusTM”) in order to eliminate zinc.
• the solid, consisting mainly of zinc, is washed twice with ethanol (120 g each wash).
• the yellow/orange colored filtrates, which still contain a yellow/white precipitate, are combined.
• the combined filtrates are filtered a second time.
• a precipitate (zinc complexed with the compound of formula (IIIb)) and/or with the compound of formula (I) and reaction by-products, can form in the filtrate. This precipitate is soluble in dimethylsulfoxide.
• the volatile compounds are separated by placing the filtrate in distillation equipment, such as a rotary evaporator, by limiting the heating to avoid the degradation of the compound of formula (IIIb) (Temperature of the boiler ⁇ 60° C., the distillation time is about 1 hour).
• the crude compound of formula (IIIb) is obtained in the form of a brown/orange solid.
• the yield of compound of formula (IIIb) obtained from the compound of formula (I) at this stage is 80%, ie 80 g.
• the crude compound of formula (IIIb) is crystallized at 25° C. from an MTBE (Methyl tert-butyl ether)/ethyl acetate (67/33 vol/vol, i.e.

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