Synthesis method for a C-glycoside

Abstract

The present invention relates to a process for the synthesis of at least one C-glycoside comprising the following successive steps: (A) the introduction into a first mechanochemical reactor, separately or previously mixed, of at least one sugar in the form of pyranose and / or furanose and of the D and / or L series, said sugar having at least one hydroxyl function at the obligatorily free anomeric position, of a first reagent which is a β-diketone and of a base, in order to form a first initial mixture; (B1) at least a first grinding of said first initial mixture at a temperature greater than or equal to 20°C, in said first mechanochemical reactor, for a residence time less than or equal to 6 hours, so as to form a ketone C-glycoside; (C) the recovery at the outlet of the first mechanochemical reactor of a final mixture.The present invention also relates to the use of the mechanochemical reactor for synthesizing a C-glycoside or a C-glycoside derivative comprising said at least C-glycoside. Figure for the abstract: no figure.

Description

Title of the invention: Process for the synthesis of a C-glycoside

[0001] Technical field to which the invention relates

[0002] The present invention relates to a method for synthesizing C-glycosides which may include a ketone function or chemical functional group.

[0003] In particular, the present invention relates to a process for the synthesis of C-glycosides which may include at least one ketone function or at least one other chemical functional group, carried out by mixing / milling (i.e.: grinding, micro-milling or extrusion) generally in a single specific mechanochemical reactor, such as for example a three-dimensional wet-phase mill.

[0004] The present invention also relates to the use of this mechanochemical reactor to synthesize, during one and generally several sequential reactions, at least one C-glycoside, without the need to remove the reaction media or media from the mechanochemical reactor. Technological background

[0005] Carbohydrates, also known as hydrates of carbon, with the general formula Cn(H2O)n, are a family of abundant natural compounds found in various forms: monomers, oligomers, and polymers. This bioresource is the subject of intense research due to the numerous applications of its derivatives, particularly C-glycosides. For example, the molecule C-[3-D-xylopyranoside-2-(5')-hydroxypropane (Pro-Xylane®), developed by L'Oréal, is a C-glycoside derivative prepared from D-xylose and is recognized as an anti-aging molecule that stimulates the biosynthesis of glycosaminoglycans of interest.

[0006] As is known, C-glycosides are a class of compounds in which a carbohydrate is linked to an aglycone or another carbohydrate via a C-C bond instead of the usual C-O glycosidic bond. This conversion makes C-glycosides remarkably stable to both chemical and enzymatic hydrolysis.

[0007] Several methodologies have been developed for the preparation of C-glycosides.

[0008] Most of the preparation of such compounds often involves multi-step reactions that require the protection of the sugar's hydroxyl groups and the activation of the anomeric position by the addition of a suitable activatable group or by oxidation. These transformations consume large quantities of reagents as well as organic solvents, notably impacting the E factor (i.e., the mass ratio of waste to desired product). Indeed, in general, the synthesis is carried out conventionally in an H2O-organic solvent medium (such as methanol MeOH, tetrahydrofuran THF, dimethylformamide DMF, acetonitrile CH3CN, dimethyl sulfoxide DMSO, ethanol EtOH) by reacting a protected sugar (monosaccharide) with pentane-2,4-dione (i.e., acetylacetone) present in excess (molar ratio sugar / acetylacetone = 1 / 2) with a base, also present in excess in the reaction medium (molar ratio sugar / base = 1 / 15) for a reaction time of approximately 48 hours. The reaction can be heated (e.g. up to 90°C) or not (Schoenenberger, B.; Summermatter, W.; Ganter, C., Enantioselective Synthesis of Pseudomonic Acids. I. Synthesis of Key Intermediates, Helvetica Chimica Acta 1982, 65 (7), 2333 - 2337 or Howard, S.; Withers, SG, Bromoketone C -glycosides, a new class of beta-glucanase inactivators J. Am. Chem. Soc. 1998, 120, 10326-10331).

[0009] The conventional synthesis of C-glycosides described above thus presents certain drawbacks. It is carried out in batch mode rather than continuously, is complex to implement, time-consuming, and not very environmentally friendly. In particular, the two publications mentioned above describe multi-step syntheses involving protection / deprotection reactions of sugar hydroxyl groups to access C-glycoside derivatives, and the use of either harsh conditions and / or toxic reagents. Schoenenberger et al. first describe the protection of D-ribose as an acetal, which then undergoes a Wittig reflux reaction in acetonitrile. The intermediate acyclic derivative is then treated with MeONa to yield a mixture of acetylated or unacetylated C-riboside.Howard et al. use a tetrabenzylated allyl-[3-C-glucoside] as a starting substrate, which undergoes epoxidation with mCPBA followed by reduction with DIBAL-H and finally Jones oxidation with chromic acid. The [3-C-glucoside of interest is finally obtained after deprotection of the benzyl groups. These syntheses are not environmentally friendly.

[0010] The publication by Lubineau et al. in 2000 (Lubineau, Rodrigues; Canac; A convenient, one-step, synthesis of beta-C-glycosidic ketones in aqueous media, Chemical Communications 2000, (20), 2049 - 2050) describes the synthesis of [3-DC -glycosides ketone by Knoevenagel condensation from pentane-2,4-dione with an unprotected sugar, no longer in an organic solvent, but in an aqueous alkaline medium.

[0011] The synthesis reaction according to Lubineau et al. is illustrated in [Fig. 1].

[0012] The Knoevenagel condensation of pentane-2,4-dione with the sugar allows the formation of the intermediate compound named 11 in [Fig. 1] above by a nucleophilic addition of the pentane-2,4-dione anion formed in situ to the sugar aldehyde, which is followed by a [3-elimination of water to form the enone compound 12. This intermediate 12 then undergoes an intramolecular Michael addition leading to the cyclization of the intermediate C-glycoside 14, most likely as a mixture of the four possible stereoisomers: α,[3-furanosides and α,[3-pyranosides (since when the reaction is carried out at room temperature, a a mixture of the four isomers 15a, b, c, d in which the [3^C-pyranoside 15d] predominates, is obtained by retro-Claisen aldol condensation with concomitant elimination of sodium acetate). Basic catalysis gives almost exclusively the formation of the thermodynamic stereoisomer [3-glucopyranoside 15d].

[0013] This process, however, has the disadvantage of being carried out in the laboratory using conventional glassware in batch mode. It is therefore less suitable for the industrial production of a 3-DC-glycoside ketone. The time required to carry out the synthesis is generally 6 to 12 hours in water at a temperature of around 90°C.

[0014] Following this publication, the commercialization of C-glycosides was undertaken, notably by the company L'OREAL for the production of Pro-Xylane® and many other compounds. French patent FR 2 818 547, also filed in 2000, describes in particular a process for manufacturing C-glycoside derivatives that may have the following formula (I'): [Chem.l] S'^X—R (!')

[0015] in which S is a monosaccharide or a polysaccharide;

[0016] the S-CH2-X bond represents a bond of C-anomeric nature;

[0017] X can be a -CO- group;

[0018] R represents a functional group, such as an alkyl group.

[0019] The process for preparing these C-glycoside derivatives consists in particular of:

[0020] - to be dissolved in water or in a mixture of water and a solvent an organic miscible in water, preferably a protic polar solvent and advantageously tetrahydrofuran, dioxane, A-methylpyrrolidine, dimethylformamide, acetonitrile, and / or alcohols in particular ethanol, 1 equivalent of a monosaccharide or a polysaccharide of formula S,

[0021] - to be added between 1 and 2 equivalents of a [3-diketonic compound of formula general: R"-CÛ-CHâ-WR [Chem-2]

[0022] with R as defined above and R" corresponding to the definition given above for R, with the exception of hydrogen (acetylacetone being already described in Lubineau's publication), and between 1 and 2 equivalents of an organic or mineral base, preferably mineral, and heating the reaction mixture to a temperature between 40°C and 100°C, for a period between 3 and 30 hours, preferably between 5 and 15 hours,

[0023] - then, after cooling, to wash the reaction medium with an organic solvent which can be chosen from ethyl acetate, dichloromethane, diethyl ether, dü-sopropyl ether, tert-butyl ether, methyl ethyl ketone,

[0024] - to neutralize the aqueous phase by a mineral or organic acid or by passing over an acidic resin, preferably on an acidic resin,

[0025] - to concentrate and then co-evaporate with an organic solvent selected from ethanol, the methanol, toluene and / or isopropanol,

[0026] - to dry the product obtained under vacuum, then possibly to purify it by chroma tography and / or crystallization.

[0027] The publication by Feng, W. et al. (Feng, W.; Fang, Z.; Yang, J.; Zheng, B.; Jiang, Y., Microwave-assisted efficient synthesis of aryl ketone beta-C-glycosides from un-protected aldoses. Carbohydrate Research 2011, 346 (2), 352-356) describes the synthesis of C-glycosides using microwave heating (400 W). The reaction time is reduced from 1 h to 1.5 hours depending on the starting sugar, but this synthesis requires an EtOH / H2O 4:1 mixture to achieve a yield of 98% in 1 h.

[0028] As illustrated above, the synthesis of C-glycosides and in particular of C-glycosides linked to an aglycone having a functional group of interest (i.e.: hereafter referred to as C-glycoside derivatives) has evolved little since 2011. A synthetic process that is easy to implement and allows for selective modification of the oses (i.e.: sugars) thus remains a real challenge.

[0029] There is therefore a need in the prior art to provide a new process for the synthesis of C-glycosides and its derivatives avoiding at least in part the aforementioned disadvantages.

[0030] In particular, there is a need in the prior art to provide a process for the synthesis of C-glycosides, as well as its derivatives, preferably in continuous mode, which is simple, industrially exploitable, in particular not requiring an excessively long reaction time (namely a reaction time shorter than conventional processes which varies from 6 to 48 hours).

[0031] Object of the invention

[0032] To this end, the present invention relates to a process for the synthesis of at least one C-glycoside comprising the following successive steps:

[0033] (A) the introduction into a first mechanochemical reactor, separately or pre- lable mixed, of at least one sugar in the form of pyranose and / or furanose and of series D and / or L, said sugar having at least one hydroxyl function at the obligatorily free anomeric position, of a first reagent which is a [3-diketone and of a base, in order to form a first initial mixture;

[0034] (B 1) at least a first grinding of said first initial mixture at a temperature greater than or equal to 20°C in said first mechanochemical reactor, for a residence time less than or equal to 6 hours, so as to form a C-glycoside ketone;

[0035] (C) the recovery at the outlet of the first mechanochemical reactor of a mixture final.

[0036] Other non-limiting and advantageous features of the process according to the invention, taken individually or in all technically possible combinations, are as follows:

[0037] - said first initial mixture comprises water as LAG;

[0038] - said at least first grinding of said initial first mixture is carried out at a temperature temperature ranging from 30°C to 120°C, and in particular at a temperature ranging from 40°C to 90°C;

[0039] - the residence time of said first initial mixture within said first reactor of mechanochemistry is less than or equal to 4 hours and in particular ranges from 1 minute to 3 hours;

[0040] - said at least one sugar is chosen from: a monosaccharide, an oligosaccharide having 2 to 10 sugar units or a polysaccharide having more than 11 sugar units (such as 11 to 20 or more sugar units), and any mixture thereof;

[0041] - said monosaccharide is selected from D-galactose, D-mannose, D-xylose, the D-lyxose, D-ribose, L-fucose, L-arabinose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D- or L-iduronic acid, N-acetyl-D-glucosamine, A-acetyl-D-galactosamine and advantageously designates D-glucose, D-xylose, A-acetyl-D-glucosamine or L-fucose, and very preferably D-xylose or one of their mixtures;

[0042] or

[0043] said oligosaccharide is selected from oligosaccharides containing up to 6 sugar units, such as D-maltose, D-lactose, D-cellobiose, melibiose, D-maltotriose, a disaccharide combining a uronic acid selected from D- or L-iduronic acid or D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, A-acetyl-D-galactosamine, A-acetyl-D-glucosamine, an oligosaccharide containing at least one xylose advantageously selected from xylobiose, methyl-[3-xylobioside, xylotriose, xylotetraose, xylopentaose and xylohexaose and preferably xylobiose which is composed of two xylose molecules linked by a beta-1,4 bond,

[0044] or

[0045] said polysaccharide is selected from cellulose, starch, amylose, amylopectin, galacturonan, glucuronan, chitin, chitosan, dextran, glucans, mannans, galactans, alginates, pectins, pullulan or a mixture thereof;

[0046] and one of their mixtures;

[0047] - said first reactant which is a [3-diketone] corresponds to the following formula (I): R^-CO-CHs-CO-R^ [Chem. 3] (Formula I)

[0048] in which

[0049] R1 and R2, independently of each other, represent a linear or branched alkyl, hydrofluoroalkyl, saturated or unsaturated chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl ring, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said ring or said radical being optionally interrupted by one or more heteroatoms selected from oxygen, sulfur, nitrogen, preferably R1 represents an alkyl group, such as a methyl group;

[0050] - during step (A), the concentration of said at least one sugar in said first initial mixture is greater than or equal to 100 g / L, preferably ranges from 100 g / L to 10,000 g / L, in particular ranges from 200 g / L to 3,000 g / L and typically ranges from 450 g / L to 2,800 g / L, such as 2,600 g / L;

[0051] - during step (A), the quantity of said first reactant, for one equivalent (eq.) of said at least one sugar, varies from 0.75 to 5 eq., preferably varies from 1 to 2 eq. and typically varies from 1 to 1.2 eq.;

[0052] - during step (A), the basic quantity for one equivalent (eq.) of said at least one sugar varies from 1 to 4 eq., preferably varies from 1.2 to 3 eq and typically varies from 1.2 to 2.5 eq.;

[0053] - said process comprises at least: (B2) a second grinding carried out in said first mechanochemical reactor after step (Bl) or carried out in a second mechanochemical reactor, different from the first mechanochemical reactor after step (C), from a second initial mixture comprising at least said C-Glycoside ketone previously formed at the end of step (Bl), said starting C-glycoside ketone and a second starting reagent, so as to functionalize said starting C-glycoside ketone and obtain another C-glycoside;

[0054] - said second grinding (B2) is carried out directly after step (B1) and in said first mechanochemical reactor;

[0055] - said functionalization reaction is chosen from:

[0056] * an aldol condensation-crotonization reaction, so as to obtain a C-glycoside exhibiting an unsaturated α[3] ketone function, such as a C-glycoside-enone,

[0057] * an addition reaction of O-, N-, S-, C-nucleophiles, preferably of A- nucleophilic aliphatic or aromatic, in order to obtain a C-glycoside imine;

[0058] - during step (B2), said second starting reagent is chosen from:

[0059] * a compound of formula (II) D, [Chem. 4] h £ P" it Formula (0) J R3

[0060] wherein R3 is chosen from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R3 is a hydrogen atom and R4 is chosen from the group consisting of: -CHO, CH2NH2; preferably, said second starting reagent is chosen from: benzaldehyde or benzylamine; and / or

[0061] * a compound of formula (III) , " " [Chem. 5 R--CHO (Formula hl)

[0062] wherein R5 is selected from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms;

[0063] - said process includes a step (D) of neutralizing the final product;

[0064] - said first or second mechanochemical reactor is selected from:

[0065] * a planetary ball mill,

[0066] * a vibrating crusher (i.e.: vibro-crusher or vibrating crusher);

[0067] *a three-dimensional wet-phase mill with or without balls;

[0068] * an extruder.

[0069] The present invention also relates to the use of a first and / or a second mechanochemical reactor, to synthesize a C-glycoside, such as a C-glycoside ketone, a derivative of C-glycoside ketone (generally from the starting C-glycoside ketone), such as a C-glycoside enone, or a C-glycoside imine.

[0070] Of course, the different features, variants and embodiments of the invention can be combined with each other in various ways insofar as they are not incompatible or mutually exclusive. Description of the figures

[0071] In addition, various other features of the invention become apparent from the attached description made with reference to the drawings which illustrate non-limiting embodiments of the invention and where:

[0072] [Fig-1] represents the synthesis reaction of C-glycosides ketone according to a process of earlier art, the publication by Lubineau et al. in 2000;

[0073] [Fig.2] represents a cross-sectional view, along a cutting plane passing through the longitudinal axis XX, of an embodiment of the invention in which the mechanical reactor nochimie is a three-dimensional wet-phase grinder;

[0074] [Fig.3] represents another embodiment of the invention in which the mechanochemical reactor is a twin-screw co-rotating extruder with double raw material inlets;

[0075] [Fig.4] represents the mass spectrum of the sample obtained according to another embodiment of the synthesis process according to the invention in which the first mechanochemical reactor is selected from a co-rotating twin-screw extruder; and

[0076] [Fig.5] (a) represents the 13C NMR spectrum of the example according to the invention obtained in a planetary mill (example 3, Table 2) and (b) represents the 13C NMR spectrum of the sample from [Fig.4].

[0077] It should be noted that, in these figures, the structural and / or functional elements common to the different variants may have the same references.

[0078] Detailed description of an example embodiment 1°) Definitions

[0079] In the present invention, unless otherwise specified, the term "include" and its derivatives shall be understood as non-limiting and not excluding the presence of other components or steps. In certain particular embodiments, the term "include" may be understood as "consisting essentially of" or "being made up of".

[0080] According to the invention, "by C-glycoside" is meant a class of compounds in which a sugar, such as a monosaccharide, an oligosaccharide or a polysaccharide, is linked to an aglycone or another carbohydrate via a C-C bond instead of the usual C-O glycosidic bond.

[0081] According to the invention, by "C-glycoside ketone" is meant the C-glycoside formed from step (Bl) of the process according to the invention and comprising at least one ketone function which is not present directly on or directly linked to the sugar ring (i.e. monosaccharide, oligosaccharide or polysaccharide). In particular, the ketone function is at position 2 of the propyl chain (aglycone) linked to the anomeric carbon of the sugar at position a or [3.

[0082] “By a ketone C-glycoside derivative” or by “C-glycoside of interest”, we mean according to the invention a C-glycoside ketone which has undergone at least one chemical functionalization reaction, for example with an aromatic or aliphatic aldehyde group in order to obtain a C-glycoside-enone or with an aliphatic or aromatic A^-nucleophilic group in order to obtain a C-glycoside-imine.

[0083] Hereinafter, "LAG" (from the English "Liquid-assisted grinding") refers to a liquid additive characterized by a value of q that must be between 0 (not inclusive) and 2, q being defined as the ratio of liquid additive in qL to the sum of reactants in mg. LAG corresponds to a small quantity of liquid (generally of water) which typically allows the progress of synthesis reactions to be accelerated.

[0084] For the remainder of the description, unless otherwise specified, the indication of a range of values ​​"from X to Y" or "between X and Y" in the present invention is understood to include the values ​​X and Y. 2°) Synthesis process

[0085] The Applicant has focused on developing a new process for the synthesis of C-glycoside and in particular of a ketone C-glycoside or one of its derivatives (i.e.: a ketone C-glycoside functionalized by another chemical functional group).

[0086] As mentioned above, the process according to the invention refers to a process for the synthesis of at least one C-glycoside comprising the following successive steps:

[0087] (A) the introduction into a first mechanochemical reactor, separately or pre- lable mixed, of at least one sugar in the form of pyranose and / or furanose and of series D and / or L, said sugar having at least one hydroxyl function at the obligatorily free anomeric position, of a first starting reagent which is a [3-diketone and of a base, in order to form a first initial mixture;

[0088] (B 1) at least a first grinding of said first initial mixture at a temperature greater than or equal to 20°C, in said first mechanochemical reactor, for a residence time less than or equal to 6 hours, so as to form a C-glycoside ketone;

[0089] (C) the recovery at the outlet of the first mechanochemical reactor of a mixture final.

[0090] The Applicant has thus developed a process which, surprisingly and unexpectedly, allows the synthesis of C-glycosides, and in particular a ketone C-glycoside, at the end of step (Bl). As will be described below, the process according to the invention also allows the synthesis of other C-glycosides of interest, namely functionalized C-glycosides obtained from the ketone C-glycoside, by simply adding another starting reagent to the same mechanochemical reactor directly after carrying out step (Bl) (i.e., obtained in a sequential "one-pot" process). Indeed, the use of a mechanochemical reactor that allows continuous synthesis, such as a planetary mill, a three-dimensional wet mill (with or without grinding balls), or an extruder, enables the synthesis of the C-glycoside of interest (i.e., the functionalized C-glycoside) in a "one-pot" process.

[0091] Furthermore, the synthesis process according to the invention has the advantage of being carried out without the use of a solvent, using only a base, and advantageously (but not necessarily) also in the presence of water as a LAG, particularly when the mechanochemical reactor is chosen from a mill as defined above. Consequently, the synthesis process according to the invention is more environmentally friendly and preferentially avoids, unlike processes according to the prior art, the use of organic solvents, such as methanol, tetrahydrofuran, dimethylformamide, acetonitrile, dimethyl sulfoxide or ethanol.

[0092] Moreover, the quantities of reaction agents, such as the first starting reagent [3-diketone, the base and where applicable the second starting reagent, are relatively small (for example, on the order of, for one equivalent of sugar, 0.75 to 5 equivalents of the first starting reagent or 1 to 4 equivalents of base).

[0093] In addition, the synthesis in C-glycoside ketone or one of its derivatives is short, in general the residence time in the reactor is less than 6 hours and ranges from 1 minute to 3 hours (versus 48 hours for conventional synthesis processes in organic solvent medium or versus 6 to 12 hours for the process described in the publication by Lubineau or 1h to 1h30 under microwave irradiation described in the publication by Feng et al.).

[0094] The process according to the invention also has the advantage (depending on the choice of mechanochemical reactor used) of performing continuous flow mechanosynthesis of C-glycoside. This makes it possible to obtain a high sugar concentration (i.e., monosaccharide, oligosaccharide, or polysaccharide). Indeed, a reactor such as a three-dimensional wet mill or an extruder allows for the continuous synthesis of C-glycoside, unlike planetary or vibrating ball mills, which operate in batch production.

[0095] When the process includes at least one additional functionalization step (step B2 below), it also has the advantage of avoiding and / or reducing intermediate steps, such as purification steps. Indeed, in order to form another C-glycoside of interest (step B2), it is generally not necessary to purify the ketone C-glycoside obtained at the end of step (B1).

[0096] The Applicant has further observed, and as the experimental tests below demonstrate, that the conversions to a ketone C-glycoside or another C-glycoside of interest, such as an enone C-glycoside, were very high, at least 70%, in particular at least 85%, and even greater than or equal to 99% (depending on the experimental conditions). Thus, few or no by-products are formed during the synthesis process according to the invention, particularly at the end of step (B1) and / or at the end of step (B2).

[0097] Furthermore, the process according to the invention allows the synthesis of numerous ketone C-glycosides and C-glycosides of interest depending on the sugar initially selected, the substituents of the first starting reagent, and, where applicable, the choice of the second starting reagent (determined according to the chosen functionalization), and this in a sequential "one-pot" process. That is to say, it is possible to use the same mechanochemical reactor operating in batch mode (planetary mill, vibrating mill) or in continuous mode (three-dimensional wet mill - with or without grinding balls - or even extruder). Of course, other one-pot functional reactions can be carried out after step (B2) (milling step (B3), etc.) depending on the desired C-glycoside of interest.

[0098] The process according to the invention also has the advantages of a lower cost price (the raw materials used are widely available, non-polluting, and inexpensive) and excellent reproducibility. As mentioned above, the process according to the invention also has the advantage, in certain embodiments, of being able to be implemented continuously. These characteristics are important for industrial-scale application.

[0099] Finally, despite the numerous studies conducted on the synthesis of C-glycosides (C-glycosides ketone or its derivatives), none has suggested the aforementioned process and in particular at least one grinding step in a mechanochemical reactor from the starting reagents.

[0100] 2.1) Step (A)

[0101] As mentioned above, the C-glycoside synthesis process according to the invention begins with a step (A) of introducing into a first mechanochemical reactor, separately or previously mixed, at least:

[0102] - a sugar in the form of pyranose and / or furanose and of series D and / or L,

[0103] - of a first starting reagent which is a [3-diketone,

[0104] - and where appropriate of a base and water as LAG when said first The mechanochemical reactor is chosen from among a mill, and in particular a three-dimensional wet-phase mill.

[0105] All of these constituents together form a mixture, hereinafter referred to as the "first initial mixture".

[0106] In particular, the sugar has at least one hydroxyl group at the obligatorily free anomeric position. It can be selected from a monosaccharide, an oligosaccharide having from 2 to 10 sugar units or a polysaccharide having from 11 to 20 sugar units or more, and a mixture thereof.

[0107] In general, the monosaccharide may be selected from D-glucose, D-galactose, D-mannose, D-xylose, D-lyxose, L-fucose, L-arabinose, D-ribose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D- or L-iduronic acid, A-acetyl-D-glucosamine, A-acetyl-D-galactosamine, and mixtures thereof. Advantageously, the monosaccharide is selected from D-glucose, D-xylose, A-acetyl-D-glucosamine, or L-fructose, and is typically D-xylose.

[0108] In particular, the oligosaccharide may be selected from oligosaccharides containing up to 6 sugar units. By way of example, such an oligosaccharide may be selected from: D-maltose, D-lactose, D-cellobiose, D-maltotriose, D-melibiose, a disaccharide combining a uronic acid selected from D- or L-iduronic acid or D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, IV-acetyl-D-galactosamine, or IV-acetyl-D-glucosamine, and an oligosaccharide containing at least one xylose advantageously selected from xylobiose, methyl-[3-xylobioside], xylotriose, xylotetraose, xylopentaose, and xyl-lohexaose. The oligosaccharide may in particular be selected from xylobiose, which is composed of two xylose molecules linked by a beta-1,4 bond.

[0109] According to the invention, the polysaccharide can be selected from cellulose, starch, amylose, amylopectin, galacturonan, glucuronan, chitin, chitosan, dextran, glucans, mannans, galactans, alginates, pectins, pullulan or a mixture thereof.

[0110] Typically, the concentration of sugar or mixtures of sugars (monosaccharide, oligosaccharide and / or polysaccharide) in the first initial mixture is greater than or equal to 100 g / L, preferably from 100 g / L to 10,000 g / L, in particular from 200 g / L to 3,000 g / L and typically from 450 g / L to 2,500 g / L.

[0111] According to the invention, "a concentration of sugar or sugar mixtures in the first initial mixture is greater than or equal to 100 g / L" includes the following values ​​(g / L) and all intervals between these values: 100; 110; 120; 130; 140; 150; 160; 170; 180; 200; 250; 300; 350; 400; 450; 500; 550; 600; 650; 700; 750; 800; 850; 900; 950; 1000; 1100; 1200; 1300; 1400; 1500; 1600; 1700; 1800; 1900; 2000; 2500; 3000; 3500; 4000; 4500; 5000; 5500; 6000; 6500; 7000; 7500; 8000; 8500; 9000; 9500; 10,000; 10,100; 10,200, etc.

[0112] The first starting reagent is a [3-diketone corresponds to the following formula (I): [Chem .3] R <CO-CH3-CO-Rk (foîmule Q

[0113] in which

[0114] R1 and R2, independently of each other, represent a linear or branched alkyl, hydrofluoroalkyl, saturated or unsaturated chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl ring, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said ring or said radical being optionally interrupted by one or more heteroatoms selected from oxygen, sulfur, nitrogen.

[0115] Preferably, R1 represents an alkyl group, such as a methyl group.

[0116] According to a preferred embodiment, [3-diketone corresponds to the compound pentane-2,4-dione (also called acetylacetone).

[0117] In general, the quantity of said first starting reagent, for one equivalent (eq.) of said at least one sugar, varies from 0.75 to 5 eq., preferably varies from 1 to 2 eq and typically varies from 1 to 1.2 eq.

[0118] According to the invention, "a quantity of said first starting reagent, for one equivalent (eq.) of said at least one sugar which varies from 0.75 to 5 eq." comprises the following values ​​(in eq.) and all intervals between these values: 0.75; 0.80; 0.85; 0.90; 0.95; 1.00; 1.10; 1.20; 1.30; 1.40; 1.50; 1.60; 1.70; 1.80; 1.90; 2.00; 2.10; 2.20; 2.30; 2.40; 2.50; 2.60; 2.70; 2.80; 2.90; 3.00; 3.10; 3.20; 3.30; 3.40; 3.50; 3.60; 3.70; 3.80; 3.90; 4.00; 4.10; 4.20; 4.30; 4.40; 4.50; 4.60; 4.70; 4.80; 4.90; 5.00.

[0119] The initial first mixture also includes a base. By way of example, the base may be chosen from the group consisting of: NaHCO3, Na2CO3, NaOH or one of their combinations and is preferably NaOH or Na2CO3.

[0120] Typically, the basic quantity for one equivalent (eq.) of said at least one sugar varies from 1 to 4 eq., preferably varies from 1.2 to 3 eq and typically varies from 1.2 to 2.5 eq.

[0121] According to the invention, "a basic quantity for one equivalent (eq.) of said at least one sugar which varies from 1 to 4 eq." comprises the following values ​​(in eq.) and all intervals between these values: 1; 1.10; 1.20; 1.30; 1.40; 1.50; 1.60; 1.70; 1.80; 1.90; 2.00; 2.10; 2.20; 2.30; 2.40; 2.50; 2.60; 2.70; 2.80; 2.90; 3.00; 3.10; 3.20; 3.30; 3.40; 3.50; 3.60; 3.60; 3.70; 3.80; 3.90; 4.00.

[0122] In general, said first initial mixture comprises water as LAG.

[0123] As will be detailed below, when the mechanochemical reactor is chosen from a mill (such as a three-dimensional wet mill, a planetary mill, or a vibrating mill), the initial mixing may also include water in the form of LAG. By way of example, in a planetary mill, the volume of LAG (H2O) may correspond to 0.4 mL for a 20 mL grinding bowl loaded with 80 5 mm balls.

[0124] These various starting reagents can be introduced into the mechanochemical reactor separately or have been previously mixed. In this case, the initial mixture can be contained in a vessel. One or more peristaltic pumps are generally used to introduce these starting reagents or the initial mixture to an inlet of the mechanochemical reactor.

[0125] In general, the mechanochemical reactor has at least one grinding chamber having at least one inlet into which these starting reagents / initial first mixture are introduced, and an outlet so as to recover the desired C-glycoside (C-glycoside ketone or one of its derivatives).

[0126] 2.2) Step (B 1)

[0127] Once the first initial mixture is introduced into the grinding chamber of the reactor, the first grinding stage (Bl) begins.

[0128] This initial first mixture is ground at a temperature greater than or equal to 20°C, in said first mechanochemical reactor.

[0129] According to the invention, "temperature greater than or equal to 20°C" means that the synthesis process, and in particular step (Bl), can be carried out at ambient temperature and that therefore no heating device is necessary / essential. A heating device means a heating means provided within the mechanochemical reactor chamber or a heating means located outside / around the mechanochemical reactor chamber. In general, the grinding reaction (Bl) is slightly exothermic and heating is observed. Thus, the temperature within the mechanochemical reactor chamber during synthesis (Bl) is around 30 to 35°C (this is an inherent temperature of the reaction (Bl) and not the application of a reaction temperature; the starting reagents or the initial mixture do not need to be heated, they are introduced at ambient temperature).: room temperature where the reaction takes place, which is generally 20-25°C).

[0130] Also, according to the invention, "at a temperature greater than or equal to 20°C" includes the following values ​​(in °C) and all intervals between these values: 20; 21; 25; 30; 35; 40; 45; 50; 55; 60; 65; 70; 75; 80; 85; 90; 95; 100; 105; 110; 115; 120; 125; 130; 135; 140, etc.

[0131] According to another embodiment, it is possible to provide a heating device inside or outside the mechanochemical reactor.

[0132] According to this embodiment, the reaction temperature during the first grinding step (Bl) can range from 30°C to 120°C and in particular from 40°C to 90°C. By a temperature ranging from 30°C to 120°C, we mean all intervals between these values ​​(as described above).

[0133] The use of a heating device makes it possible to reduce the residence time of the first initial mixture during step (Bl) and also to improve the yield of C-Glycoside ketone.

[0134] The residence time of the first initial mixture during this first grinding step (Bl) is less than or equal to 6 hours.

[0135] According to the invention, "residence time" means the time in seconds, minutes, or hours that the initial mixture is maintained within the grinding chamber of the mechanochemical reactor. In general, the residence time corresponds to the reaction time allowing the synthesis into a C-glycoside ketone with preferably a conversion of at least 75%, in particular at least 80%, and typically at least 90%, or even better, 99%.

[0136] Also according to the invention, "for a residence time less than or equal to 6 hours" includes the following values ​​and all intervals between these values: 6 hours; 5.5 hours; 5 hours; 4.5 hours; 4 hours; 3.5 hours; 3 hours; 2.5 hours; 2 hours; 1.5 hours; 1 hour; 50 minutes; 45 minutes; 40 minutes; 35 minutes; 30 minutes; 25 minutes; 20 minutes; 15 minutes; 10 minutes; 9 minutes; 8 minutes; 7 minutes; 6 minutes; 5 minutes; 4 minutes; 3 minutes; 2 minutes; 1.5 minutes or 1 minute.

[0137] In general, the residence time of the first initial mixture in the grinding chamber of the first mechanochemical reactor during step (Bl) is less than 4 hours, and in particular ranges from 1 minute to 3 hours.

[0138] At the end of this first grinding step (Bl), a C-glycoside ketone is obtained.

[0139] In general, depending on the reaction parameters (residence time, reaction temperature during step (Bl), mechanochemical reactor chosen, etc.), the conversion of the initial mixture to C-glycoside ketone is very good and is greater than or equal to 70%, preferably greater than or equal to 75%, and typically greater than or equal to 80%. This conversion is estimated by comparing the H1α and [3] signals of the remaining sugar and the HT signal of the C-glycoside formed by proton NMR in D2O.

[0140] Depending on the type of mechanochemical reactor chosen, the grinding step (Bl) can be carried out continuously in one or more passes (pendulum or recirculating mode) or in batch mode. For example, continuous mode can be achieved with a three-dimensional wet mill or an extruder, while batch mode is achieved with a planetary or vibrating mill.

[0141] Preferably, the first mechanochemical reactor is chosen from a three-dimensional wet-phase mill, a planetary mill or an extruder.

[0142] 2.3) Step (C) following step (Bl)

[0143] According to a first embodiment, the desired final C-glycoside is the C-glycoside ketone.

[0144] According to this variant, once the first grinding step has been carried out (Bl), the product from this step (hereafter referred to as the final composition) and comprising mainly a C-glycoside ketone (i.e.: estimated conversion of at least 70%) is recovered at the outlet of the first mechanochemical reactor.

[0145] This final composition may possibly include traces of the starting reagents which have not reacted, such as sugar, base, etc., or a by-product, such as a synthesis intermediate, particularly if the reaction temperature, residence time or concentrations of the starting reagents were not within the ideal reaction ranges.

[0146] Thus, several optional steps are possible in order to extract the C-glycoside ketone.

[0147] Optionally, after this recovery step (C), the process according to the invention may include a step (D) of neutralization or acidification of the final composition comprising the C-glycoside ketone.

[0148] This neutralization or acidification step (D) may include contacting the final product (aqueous phase including the C-glycoside) with an acidic agent, such as a mineral (HCl solution) or organic acid, or by passing it over an acidic resin, so as to obtain a final solution having a pH less than or equal to 7, preferably less than or equal to 4, typically less than or equal to 3 and typically around 1.

[0149] Then, the synthesis process may optionally include a concentration step (E).

[0150] Finally, the synthesis process may optionally include a step (F) of vacuum drying of the product obtained or lyophilization to remove residual water, and then possibly a purification step by silica gel chromatography and / or crystallization.

[0151] These techniques are well known to those skilled in the art and will not be described further below.

[0152] C-glycosides ketone having the following general formula (formula (IV)) can be obtained according to the process according to the invention: _ __ . „.. [Chem.6] SkCrts-Cü-R- [Formula IV]

[0153] in which

[0154] S represents the sugar as defined above, i.e.: in the form of pyranose and / or furanose and of series D and / or L whose anomeric carbon is linked to the CH2-CO-R group;

[0155] R2 is as defined above.

[0156] By way of example, the following C-glycosides ketone can be obtained according to the method of the invention:

[0157] -lC-([3-D-glucopyranosyl)-propan-2-one;

[0158] -1 -C-([3-D-galactopyranosyl)-propan-2-one;

[0159] -lC-([3-D-mannopyranosyl)-propan-2-one;

[0160] -1 -C-(aL-fucopyranosyl)-propan-2-one;

[0161] -1 -C-(aL-rhamnopyranosyl)-propan-2-one;

[0162] -1 -C-([3-D-xylopyranosyl)-propan-2-one;

[0163] -lC-([3-D-ribopyranosyl)-propan-2-one;

[0164] -lC-([3-D-arabinopyranosyl)-propan-2-one;

[0165] -lC-([3-D-lyxopyranosyl)-propan-2-one;

[0166] -lC-(2-deoxy-2-amino-[3-D-glucopyranosyl)-propan-2-one;

[0167] -lC-(2-deoxy-2-acetamido-[3-D-glucopyranosyl)-propan-2-one;

[0168] -lC-(2-deoxy-2-amino-[3-D-galactopyranosyl)-propan-2-one;

[0169] -lC-(2-deoxy-2-acetamido-[3-D-galactopyranosyl)-propan-2-one;

[0170] -lC-([3-D-glucopyranuronyl)-propan-2-one;

[0171] -lC-([3-D-galactopyranuronyl)-propan-2-one;

[0172] -lC-([3-D-idopyranuronyl)-propan-2-one;

[0173] - lC-[3-(aD-glucopyranosyl-(1 —>4)-D-glucopyranosyl)-propan-2-one;

[0174] - lC-[3-([3-D-glucopyranosyl-(1 —>4)-D-glucopyranosyl)-propan-2-one;

[0175] - l-C-[3-([3-D-galactopyranosyl-( 1 —>4)-D-glucopyranosyl)-propan-2-one;

[0176] -1 -C-[3-(a-D-glucopyranosyl-( 1 —>4)-a-D-gl ucopy ranosy l-( 1 —>4)-D-glucopyranosyl)- propan-2-one;

[0177] - l-C-[3-([3-D-xylopyranosyl-( 1 —>4)-D-xylopyranosyl)-propan-2-one;

[0178] - l-C-[3-([3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-( 1 —>4)-D-xylopyranosyl)-pro pan-2-one;

[0179] - l-C-[3-([3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-( 1 —>4)-D-xylopyranosyl)-pro pan-2-one;

[0180] -1 -C-[3-([3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-4- D-xylopyranosyl)-propan-2-one;

[0181] -1 -C-[3-([3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-( 1 —>4)-|3-D-xylopy ranosy 1 - (1—>4) -|3-D-xylopyranosyl-4-D-xylopyranosyl)-propan-2-one;

[0182] -1 -C-[3-([3-D-xylopyranosyl-( 1 —>4)-[3-D-xylopyranosyl-( 1 -^4)-[>-D-xylopy ranosy l-( I —>4) -[3-D-xylopyranosyl - (1 —> 4)-|3-D-xylopy ranosy 1-4-D-xylopy ranosy 1)-propan-2-one.

[0183] 2.4) Step (B2)

[0184] According to another embodiment, the desired final C-glycoside is not the ketone C-glycoside obtained at the end of step (Bl), but another C-glycoside of interest, such as a C-glycoside-enone (i.e., another chemical functionalization).

[0185] According to this variant, once the first grinding step (B1) has been carried out, a second grinding step (B2) is carried out.

[0186] According to the invention, this second grinding step (B2) is carried out after step (Bl) either in the first mechanochemical reactor, or in a second mechanochemical reactor, different from the first.

[0187] Indeed, according to one embodiment, steps (B1) and (B2) of the synthesis process according to the invention are carried out in the same mechanochemical reactor. According to this embodiment, it is therefore not necessary to extract the C-glycoside ketone obtained at the end of step (B1). The grinding step (B2) is carried out directly after the first grinding step (B1) (namely, between step (B1) and step (C)).

[0188] According to another embodiment, it is possible to carry out the first grinding (B1) in a first mechanochemical reactor and the second grinding (B2) in a second mechanochemical reactor different from the first. For this embodiment, the C-glycoside ketone recovered in step (C) is subsequently introduced into the second mechanochemical reactor (in other words, the grinding step (B2) does not take place directly after step (B1), but after step (C)).

[0189] In general, said second grinding (B2) is carried out directly after step (B1) and in said first mechanochemical reactor. This embodiment will be detailed below.

[0190] According to this preferred embodiment of the invention, it is not necessary to carry out intermediate steps between step (B1) and step (B2), such as extraction, purification, etc. Indeed, the conversion to C-glycoside ketone at the end of step (B1) is very good, and thus step (B2) can be carried out directly in the same mechanochemical reactor.

[0191] The starting reagents for carrying out this second grinding (B2) and forming hereafter the second initial mixture are as follows: the C-Glycoside ketone previously formed at the end of step (Bl), called starting C-glycoside ketone and a second starting reagent.

[0192] This second grinding (B2) allows a chemical functionalization reaction to be carried out and the said starting C-glycoside ketone to be converted into another C-glycoside of interest.

[0193] Preferably, the functionalization reaction is chosen from:

[0194] - an aldol condensation-crotonization reaction to obtain a C-glycoside exhibiting an unsaturated α[3] ketone function, such as a C-glycoside-enone

[0195] - an addition reaction of O-, N-, S-, C-nucleophiles, preferably N- nucleophilic aliphatic or aromatic, in order to obtain a C-glycoside imine.

[0196] The choice of the second starting reagent will depend on the desired C-glycoside of interest and thus on the desired functionalization on the sugar-linked aglycone.

[0197] In particular, said second starting reagent is chosen from a compound of formula (II) and / or (III) [Chem. 4]

[0198] wherein R3 is chosen from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R3 is a hydrogen atom and R4 is chosen from the group consisting of: -CHO, CH2NH2; and / or R-'-CHO Hl)

[0199] wherein R5 is selected from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms.

[0200] In particular, the second starting reagent is chosen from: benzaldehyde or benzylamine.

[0201] By way of example, if the second starting reagent is benzaldehyde, a C-glycoside-enone is formed.

[0202] By C-glycoside enone is meant a C-glycoside in which the C-anomeric bond is linked to an aglycone comprising an enone function.

[0203] According to this example of embodiment, the chemical reaction to form a C-glycoside enone can be schematically represented as follows (the first starting reagent is pentane-2,4-dione and the second starting reagent is benzaldehyde):

[0204] [Chem.7]

[0205] In particular, the amount of the second starting reagent for one equivalent (eq.) of starting C-glycoside ketone varies from 0.75 to 3 eq., preferably from 1 to 2.5 eq and typically ranges from 1 to 1.5 eq, such that 1 eq.

[0206] The second initial mixture may also include the addition of a complementary base (in addition to that already present at the end of step (Bl)). The presence or absence of the complementary base will depend on the type of mechanochemical reactor used and the choice of the second starting reagent. For example, when the second mechanochemical reactor is chosen from a three-dimensional wet mill, it is preferable to introduce a complementary base, whereas this is not always necessary with a planetary mill.

[0207] By way of example, the complementary base is chosen from the group consisting of: NaHCO3, Na2CO3, NaOH or one of their combinations. When present, the amount of complementary base for one equivalent (eq.) of C-glycoside ketone varies from 0.3 to 3 eq., preferably from 0.5 to 2 eq and typically ranges from 0.5 to 1 eq.

[0208] According to the invention, an equivalent quantity from 0.3 to 3 comprises the following values ​​and all intervals between these values ​​(in eq.): 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1.0; 1.2; 1.4; 1.6; 1.8; 2.0; 2.2; 2.4; 2.6; 2.8; 3.0.

[0209] Finally, the second initial mixture may include water as a LAG (and not as a solvent), particularly when the second mechanochemical reactor is chosen from a mill (three-dimensional mill, planetary mill, or vibrating mill). According to the preferred embodiment of the invention (B1 and B2 carried out in the same reactor), the LAG is already present in the grinding chamber, and it is therefore not necessary to add any more to carry out this step (B2).

[0210] The pH is thus greater than 7 and generally varies from 8 to 12.

[0211] As in step (A) mentioned above, the starting reagents (the second starting reagent and, if applicable, the base, or even the starting C-glycoside if the second reactor is different from the first) can be introduced into the second reactor separately or pre-mixed.

[0212] The residence time during this step (B2) of the second initial mixing within the second reactor is also less than or equal to 6 hours, preferably less than or equal to 4 hours and in particular ranging from 1 minute to 3 hours.

[0213] Also according to the invention, "for a stay time less than or equal to 6 hours" includes the following values ​​and all intervals between these values: 6 hours; 5.5 hours; 5 hours; 4.5 hours; 4 hours; 3.5 hours; 3 hours; 2.5 hours; 2 hours; 1.5 hours; 1 hour; 50 minutes; 45 minutes; 40 minutes; 35 minutes; 30 minutes; 25 minutes; 20 minutes; 15 minutes; 10 minutes; 9 minutes; 8 minutes; 7 minutes; 6 minutes; 5 minutes; 4 minutes; 3 minutes; 2 minutes; 1.5 minutes or 1 minute.

[0214] This stay time will be adjusted by a person skilled in the art according to the desired functionalization.

[0215] According to the invention, "residence time" means the time in seconds, minutes, or hours during which the second initial mixture is maintained within the grinding chamber of the mechanochemical reactor. In general, the residence time corresponds to the reaction time allowing the conversion of the C-glycoside ketone into another C-glycoside of interest (i.e., another chemical functionalization), preferably with a conversion of at least 75%, in particular at least 80%, and typically at least 90%, or even better, 99% (the conversion is estimated by proton NMR analysis of the crude in D2O).

[0216] As in step (Bl), the second initial mixture is ground at ambient temperature, namely at a temperature greater than or equal to 20°C, in said second mechanochemical reactor. The definitions (ambient temperature, temperature greater than or equal to 20°C, heating device, etc.) are the same as those indicated above and are not reproduced below.

[0217] According to one embodiment, no internal or external heating device is provided for the grinding step (B2). Generally, reaction (B2) is also slightly exothermic, and heating is observed. Thus, the temperature inside the chamber of the second mechanochemical reactor during synthesis (B2) is around 30 to 35°C (this is an inherent temperature of reaction (B2) and not the application of a reaction temperature via a heating device (the starting reactants or the second initial mixture do not need to be heated; they are introduced at ambient temperature (i.e., tem- room temperature where the reaction takes place, which is generally 20-25°C).

[0218] According to another embodiment, a heating device can be provided either inside or outside the mechanochemical reactor. According to this embodiment, the reaction temperature during the first grinding step (B2) can range from 30°C to 120°C, and in particular from 35°C to 90°C. A temperature ranging from 30°C to 50°C is understood to mean any interval between these values ​​(as described above).

[0219] The use of a heating device makes it possible to reduce the residence time of the second initial mixture during step (B2) and also to improve the yield of a C-glycoside ketone derivative.

[0220] Depending on the type of mechanochemical reactor chosen, the grinding step (B2) can be carried out continuously in one or more passes (pendulum or recirculating mode) or in batch mode. For example, continuous mode can be achieved with a three-dimensional wet mill or an extruder, while batch mode is achieved with a vibrating mill or a planetary mill.

[0221] Preferably, the second mechanochemical reactor is chosen from a three-dimensional wet-phase mill, a planetary mill or an extruder.

[0222] In general, depending on the reaction parameters (residence time, reaction temperature during step (B2), mechanochemical reactor chosen, etc.), the conversion of the second initial mixture to a C-glycoside ketone derivative is very good and is greater than or equal to 70%, preferably greater than or equal to 75%, and typically greater than or equal to 80%. This conversion is estimated by proton NMR analysis of the crude in D2O.

[0223] 2.5) Step (C) following step (B2)

[0224] Once the second grinding step (B2) has been carried out, the step (C) of recovering the final composition comprising the C-glycoside of interest, such as an enone C-glycoside or an imine C-glycoside, is carried out.

[0225] This step (C) is identical to that described above and includes, for example, a neutralization step (see paragraph 2.3) and will not be described further below. It may be adapted by a person skilled in the art.

[0226] For example, for the reaction to obtain a C-glycoside-enone, the final composition from step (B2) can be passed over an Amberlite® resin to obtain a neutral pH (of the order of 7).

[0227] By way of example, the following C-glycosides-enone can be obtained according to the process of the invention: - (E)-4-phenyl-l-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 / / -pyran-2-yl)but-3-en-2-one - (E)-4-phenyl-1-(3,4,5-trihydroxy-tetrahydro-2 / / -pyran-2-yl)but-3-en-2-one - (E)-4-(4-methoxyphenyl)-1-(3,4,5-trihydroxy-tetrahydro-2 / / -pyran-2-yl)but-3 -in-2-one - (E)-4-(4-dimethylaminophenyl)-1-(3,4,5-trihydroxy-tetrahydro-2 / / -pyran-2-yl )but-3-in-2-one.

[0228] By way of example, the following C-glycosides-imines can be obtained according to the process of the invention:

[0229] - (25,,37?,45,,57?)-2-((£')-2-(benzylimino)propyl)tetrahydro-2H-pyran-3,4,5-triol

[0230] - (25,,37?,45,,57?)-2-((£')-2-(tetradecylimino)propyl)tetrahydro-2H-pyran-3,4,5-triol.

[0231] Obviously, one or more other grinding steps can be carried out directly after step (B2) in order to form one or more other successive functionalizations of the C-glycoside of interest obtained at the end of step (B2).

[0232] 3) Mechanochemical reactors suitable for carrying out the process according to the invention

[0233] According to the invention, the mechanochemical reactor(s) that can be used to carry out the process according to the invention are as follows:

[0234] - of the type of mill operating in continuous mode like a planetary ball mill or a three-dimensional wet-phase crusher or;

[0235] - of the type of mill operating in batch mode like a planetary ball mill, or a vibrating crusher

[0236] - of the 'extruder type such as a co-rotating twin-screw extruder.

[0237] These different reactors will be described below.

[0238] 3.1) Planetary ball mill

[0239] In a known manner, a planetary ball mill comprises one or more grinding bowls arranged on a solar wheel. Each bowl or bowls comprise grinding balls. The grinding bowls are arranged eccentrically on the solar wheel of the planetary ball mill.

[0240] The solar wheel rotates in the opposite direction to the grinding bowls, in a ratio of l:-2, 1:-2.5, or l:-3. Under the effect of the centrifugal forces generated by the rotation, the balls are set in motion and strike the inner wall of the bowl after passing through the material to be ground. The grinding is essentially carried out by impact and friction.

[0241] By way of example, the Fritsch PULVERISETTE 7 premium line (P7PL) planetary mill is suitable for carrying out the process according to the invention.

[0242] In particular, this type of planetary mill comprises two stainless steel bowls that allow two reactions to be carried out in parallel. The bowl can have a capacity of 20 mL and contain 60 to 100 beads, preferably 80 beads of 5 mm diameter or 10 beads of 10 mm diameter. A counterweight is placed in the mill during using a single bowl. There are also larger planetary grinders with bowls of a capacity of 45 mL which are loaded with 180 balls of 5 mm diameter or 18 balls of 10 mm diameter.

[0243] Preferably, the balls generally have a diameter ranging from 1 to 10 mm, typically a diameter of 5 mm. They are generally made of stainless steel.

[0244] To carry out the process according to the invention, and in particular the grinding step (Bl), the initial mixture comprises at least the first starting reagent [3-diketone], the base, and a small amount of water (LAG). This initial mixture is introduced into the bowl of the planetary ball mill. For this step (Bl) in the planetary ball mill, it is generally necessary to add a small amount of liquid to improve the reactivity of the synthesis. The LAG could represent, for example, 0.4 mL for a 20 mL grinding bowl loaded with 80 5 mm balls.

[0245] The reaction parameters are advantageously as follows when the first mechanochemical reactor is chosen from a planetary ball mill:

[0246] - the concentration of sugar or mixture of sugars (monosaccharide, oligosaccharide) saccharide and / or polysaccharide) in the initial first mixture is greater than or equal to 250 g / L, preferably ranges from 1000 g / L to 1000 g / L, in particular ranges from 2000 g / L to 3000 g / L and is typically 2600 g / L;

[0247] - the quantity of said first starting reagent, for one equivalent (eq.) of said at least a sugar, varies from 0.75 to 5 eq., preferably varies from 0.8 to 2 eq and typically varies from 1 to 1.2 eq;

[0248] - the basic quantity for one equivalent (eq.) of said at least one sugar varies from 1 to 4 eq., preferably varies from 1.2 to 3 eq and typically varies from 1.2 to 2.0 eq.;

[0249] - The LAG has a value of q preferably ranging from 0 to 2, preferably in less than or equal to 1 and typically less than or equal to 0.2;

[0250] - reaction (B 1) is carried out without the use of an external heating device (the planetary ball mill does not usually include a heating device);

[0251] - the first initial mixture is thus introduced and ground during step (B 1) at tem ambient temperature, around 20°C-25°C (however, heating is observed during reaction (Bl) and the temperature inside the mill can rise to 30-35°C);

[0252] - the residence time of the first initial mixture during this first step of grinding (B 1) is less than or equal to 6 hours, preferably goes from 90 minutes to 4 hours and typically goes from 2 hours to 3.5 hours;

[0253] - the cycles number from 4 to 50, in particular from 10 to 45 and typically from 20 at 40, each cycle having a duration of approximately 1 to 10 minutes, typically 4 to 8 minutes, such as 5 minutes, a pause time ranging from 5 seconds to 2 minutes, typically 1 minute is taken between each cycle;

[0254] - the rotation speed of the bowls varies preferentially from 800 rpm to 200 rpm, in particular from 600 rpm to 300 rpm and typically from 500 rpm to 300 rpm, as well as 400 rpm;

[0255] - the conversion of the initial mixture into C-glycoside ketone ranges from 70 to 100%.

[0256] In order to carry out the possible grinding step (B2), the second starting reagent is generally introduced into the bowl where the C-glycoside ketone previously formed at the end of step (Bl) is already located, so as to form the second starting mixture.

[0257] The reaction parameters are advantageously as follows when the second mechanochemical reactor is chosen from a planetary ball mill:

[0258] - the quantity of said second starting reagent, for one equivalent (eq.) of said at less C-glycoside ketone starting varies from 0.75 to 3 eq., preferably varies from 1 to 2.5 eq and typically varies from 1 to 1.5 eq.;

[0259] - the addition of a supplementary base is not necessarily useful to achieve this step (B2);

[0260] - Similarly, it is not necessary to add water in the form of LAG to complete this step (B2);

[0261] - reaction (B2) is carried out without the use of an external heating device (the planetary ball mill does not usually include a heating device);

[0262] - the second initial mixture is thus introduced and ground during step (B2) at tem ambient temperature, around 20°C-25°C (however, heating is observed during reaction (B2) and the temperature inside the grinder can rise to 30-35°C);

[0263] - the residence time of the second initial mixture during this second step of grinding (B2) is less than or equal to 6 hours, preferably goes from 20 minutes to 3 hours and typically goes from 30 minutes to 1.5 hours, such as 1 hour;

[0264] - the rotation speed of the bowls varies preferentially from 800 rpm to 200 rpm, in particular from 600 rpm to 300 rpm and typically from 500 rpm to 300 rpm, as well as 400 rpm;

[0265] - the conversion of the second initial mixture into a C-glycoside ketone derivative goes from 70 to 100%.

[0266] 3.2) Three-dimensional wet-phase crusher, i.e., in the presence of water as that LAG

[0267] Such a crusher will be described with reference to [Fig.2].

[0268] As illustrated in this figure, the three-dimensional crusher 1 comprises at least:

[0269] - a stationary grinding chamber 2 of generally cylindrical shape extending along a longitudinal axis XX, said stationary chamber 2 being preferably filled at least partially with grinding balls (not shown) and comprising: at a first end 3 at least one inlet 5 for introducing the first initial mixture or the second initial mixture, and at a second end 4, an outlet 6 comprising a separation means 7 suitable for discharging only the final mixture thus formed into said chamber 2; and

[0270] - an agitator 8, disposed in the stationary grinding chamber, presented under in the form of an elongated rod along the longitudinal axis XX, said agitator 8 being capable of setting in motion the microbead / starting suspension assembly.

[0271] In particular, inlet 5 is generally connected to at least one peristaltic pump (not shown). This pump brings the starting reagents / first initial mix or second initial mix, contained for example in one or more containers, such as one or more tanks, into the grinding chamber 2 via inlet 5. Furthermore, during the operation of the three-dimensional mill, the pump brings the starting reagents / first initial mix or second initial mix at a certain adjustable flow rate, hereinafter referred to as the "flow rate." This flow rate also creates a current in the grinding chamber 2, which carries the starting suspension from inlet 5 to outlet 6.

[0272] The outlet 6 of the grinding chamber 2 includes in particular the separation system 7 which allows the separation of any beads from the final composition obtained at the end of step (B1) or (B2) comprising mainly the C-glycoside (C-glycoside ketone or derivative of C-glycoside ketone), the LAG and possibly the raw material(s) which have not reacted.

[0273] The inner wall 9 of the grinding chamber 2 comprises, according to a first embodiment, a smooth inner surface. However, according to an alternative embodiment which will be described below, fingers 11 may be provided on this inner surface 9.

[0274] As mentioned above, inside the grinding chamber 2 is arranged the agitator 8 which, in addition to the flow rate, also allows the starting suspension to be set in motion.

[0275] In particular, the agitator 8 is able to rotate around the X axis via a rotating shaft (14, [Fig.3]) to impart a swirling motion within the grinding chamber 2 to the first or second initial mixture and thus carry out intense grinding between this first or second initial mixture and possibly the balls present in the chamber 2 along the internal wall 9 of this chamber 2.

[0276] In general, the crusher suitable for carrying out the process according to the invention comprises a crushing chamber having a diameter of 75 mm to 300 mm and a length of 80 mm to 900 mm, and an agitator having a size ranging from 65 mm to 260 mm. Thus, the volume of the crushing chamber varies from 0.35 L to 600 L, preferably from 0.35 L to 62 L.

[0277] The geometry of the grinding chamber and agitator can be adjusted by a person skilled in the art according to the desired conversion, as well as the time of desired reaction. For example, it is also possible that the grinding chamber 2 includes an accelerator in order to improve the grinding of the starting suspension.

[0278] According to a first embodiment, the grinding chamber 2 does not include grinding balls.

[0279] According to a second embodiment, the grinding chamber 2 comprises grinding balls.

[0280] When present, the beads housed in the grinding chamber 2 and suitable for the process according to the invention are substantially spherical in shape and have an average diameter ranging from 0.05 mm to 4 mm, preferably from 0.2 to 3 mm, in particular from 0.3 to 2 mm, and typically in the range of 0.5 to 1 mm. Preferably, the diameter of the microbeads is less than or equal to 1 mm.

[0281] They are preferably chosen from balls having high hardness and relatively good resistance to abrasion.

[0282] In particular, the balls have a Vickers hardness measured according to EN ISO 6507-1 greater than or equal to 900 HV1, preferably from 900 HV1 to 1600 HV1, typically from 1000 to 1400 HV1.

[0283] Advantageously, they exhibit a high actual density. In general, the microbeads according to the invention have an actual density greater than or equal to 2 g / cm3, in particular ranging from 2 to 15 g / cm3, preferably from 3 to 12 g / cm3, and typically from 4 to 10 g / cm3.

[0284] Thus, the beads according to the invention can be ceramic beads (zirconium oxide ZrO2, zirconium silicate ZrSiO4); steel microbeads, tungsten carbide microbeads, glass microbeads, or a combination thereof. Preferably, the beads are ceramic because they do not generate pollution through wear. In particular, the beads are made of zirconium oxide.

[0285] In particular, the beads represent, in volume, in relation to the total volume of the stationary chamber 2, from 50% to 85%, preferably from 55% to 70%.

[0286] By way of example, the three-dimensional wet microbead mill suitable for carrying out the process according to the invention may correspond to mills marketed by the companies WAB, Dyno-Mill range: Multi Lab, ECM and KD, NETZCH company, for example LABSTAR LSI, or Alpine Hosokawa, for example, Agitated Media Mill AHM.

[0287] For example, a three-dimensional mill marketed by the company WAB (Willy A. Bachofen SARL) of type AP05 has an agitator having the following characteristics: for a frequency of 80 Hz, a speed in revolutions per minute of 4800 and a peripheral speed in m / s of 16.0; while a mill of type AP2, for a frequency of 70.8 Hz, has a speed in revolutions per minute of 2730 and a peripheral speed in m / s of 16.0.

[0288] According to one feature of the invention, the three-dimensional wet-phase mill may include an internal heating device, as described in particular in patent application WO 2019 / 228983.

[0289] The reaction parameters are advantageously as follows when the first mechanochemical reactor is chosen from a three-dimensional microbead mill:

[0290] - the concentration of sugar or mixture of sugars (monosaccharide, oligosaccharide) saccharide and / or polysaccharide) in the initial first mixture is greater than or equal to 100 g / L, preferably ranges from 100 g / L to 2000 g / L, in particular ranges from 200 g / L to 1500 g / L and typically ranges from 450 g / L to 900 g / L;

[0291] - the quantity of said first starting reagent, for one equivalent (eq.) of said at least a sugar, varies from 0.75 to 5 eq., preferably varies from 1 to 2 eq and typically varies from 1 to 1.2 eq.;

[0292] - the basic quantity for one equivalent (eq.) of said at least one sugar varies from 1 to 4 eq., preferably varies from 1 to 3 eq and typically varies from 1 to 2.0 eq.;

[0293] - The LAG has a q value preferably ranging from 0 to 2, preferably < 1 and typically < 0.2;

[0294] - reaction (B 1) can be carried out with or without the use of a heating device external, preferably the crusher does not include a heating device;

[0295] - according to this embodiment, the initial first mixture is thus introduced and stirred during step (Bl) at ambient temperature, of the order of 20°C-25°C (however, heating is observed during reaction (Bl) and the temperature inside the mill can rise to 30-35°C)

[0296] - reaction (B 1) can be carried out with the use of a heating device external (the grinder includes a heating device such as an induction heating device);

[0297] - according to this embodiment, the initial first mixture is thus introduced and stirred during the hot stage (Bl), that is to say at a temperature greater than or equal to 30°C, preferably greater than or equal to 40°C and ideally greater than or equal to 90°C in order to obtain a better yield (for example, at a temperature ranging from 50°C to 120°C, preferably ranging from 60°C to 110°C, typically ranging from 80°C to 100°C, such as 90°C);

[0298] - this embodiment has the advantage of providing a reaction temperature precise, regardless of the flow rate or temperature of the starting reagents / first or second initial mixing at the mill inlet (better heating of the flow forming the initial mixture); this embodiment is also particularly suited to an embodiment where several successive grindings are carried out in one-pot;

[0299] - the residence time of the first initial mixture during this first step of grinding (Bl) is less than or equal to 6 hours, preferably ranging from 50 minutes to 4 hours and typically ranges from 1 hour to 3 hours;

[0300] - the reaction (B 1) takes place continuously, namely during the residence time determined, the product is continuously recovered at outlet 6 of the crusher (via for example a pump) and reintroduced into inlet 5;

[0301] - the flow rate ranges from 50 mL / min to 500 mL / min, preferably from 60 mL / min to 300 mL / min and typically from 150 mL / min to 250 mL / min;

[0302] - the residence time is inherent to the apparent volume of any beads and the flow rate passing through;

[0303] - for example, if the total apparent volume of the beads is 270 cm3 (beads of mass apparent volumetric density of 3.7 g / cm3) and that the introduction flow rate of the first or second initial mixture is 45 L / h, i.e. 12.45 cm3 / s, then the residence time of the suspension in chamber 1 is estimated to be about 22 seconds - therefore, the residence time can be advantageously adjusted, for example by controlling the apparent volumetric density of the microbeads, as well as the flow rate;

[0304] - "Apparent volume" means the volume of the spheres including interstitial air between the beads - the apparent density is the ratio between the mass of the microbeads and the apparent volume;

[0305] - when present, the apparent volume of the microbeads ranges from 250 mL to 450 mL, preferably from 300 mL to 400 mL and is typically from 330 mL to 360 mL; this apparent volume of microbeads is suitable for example for a three-dimensional mill comprising a stationary chamber 1 of 500 m;

[0306] - the agitator 10 via its elongated rod 11 can exhibit a rotational speed su greater than or equal to 100 revolutions per minute, advantageously greater than or equal to 1000 revolutions per minute (rpm), preferably greater than or equal to 2000 revolutions per minute and typically greater than or equal to 2500 revolutions per minute;

[0307] - the peripheral speed of the agitator is greater than or equal to 6 m / s, in particular greater than or equal to 8 m / s (by "peripheral speed of the agitator", we mean the rotation speed multiplied by the circumference of the agitator disc);

[0308] - the conversion of the first initial mixture into C-glycoside ketone ranges from 80 to 100%.

[0309] In order to carry out the possible grinding step (B2), the second starting reagent is generally introduced into chamber 2 where the C-glycoside ketone previously formed at the end of step (Bl) is already located, so as to form the second initial mixture.

[0310] The reaction parameters are advantageously as follows when the second mechanochemical reactor is chosen from a three-dimensional wet-phase mill:

[0311] - the quantity of said second starting reagent, for one equivalent (eq.) of said at The starting C-glycoside ketone varies from 0.75 to 3 eq., preferably from 1 to 2.5 eq and typically varies from 1 to 1.5 eq. ;

[0312] - the base can be chosen from Na2CO3 or NaOH in a quantity for a equivalent (eq.) of said at least one C-glycoside ketone ranging from 1.2 to 1.5 eq.;

[0313] - it is not necessary to add water / LAG to perform this step (B2) (water / LAG is already present in the mill in wet phase);

[0314] - according to an alternative embodiment, reaction (B2) is carried out without the use of external heating device;

[0315] - according to this method, the second initial mixture is thus introduced and mixed during step (B2) at room temperature, around 20°C-25°C (however, heating is observed during reaction (B2) and the temperature inside the mill can rise to 30-35°C);

[0316] - according to another embodiment, reaction (B2) can be carried out using heating device (the grinder includes a heating device such as an induction heating device);

[0317] - according to this embodiment, the second initial mixture is thus introduced and brewed during step (B2) hot, that is to say at a temperature greater than or equal to 30°C, preferably greater than or equal to 40°C and ideally greater than or equal to 90°C in order to obtain a better yield.

[0318] - the residence time of the first initial mixture during this first step of grinding (Bl) is less than or equal to 6 hours, preferably goes from 1 minute to 4 hours and typically goes from 1 minute to 3.0 hours;

[0319] - reaction (B2) takes place continuously, namely during the residence time determined, the product is continuously recovered at outlet 6 of the crusher (via for example a pump) and reintroduced into inlet 5;

[0320] - the flow rate during reaction (B2) ranges from 50 mL / min to 500 mL / min, from preferably from 60 mL / min to 300 mL / min and typically from 150 mL / min to 250 mL / min;

[0321] - the residence time is inherent to the apparent volume of any beads and the flow rate passing through;

[0322] - when present, the apparent volume of the microbeads ranges from 250 mL to 450 mL, preferably from 300 mL to 400 mL and is typically from 330 mL to 360 mL;

[0323] - the agitator 10 via its elongated rod 11 can exhibit a rotational speed su greater than or equal to 100 revolutions per minute, advantageously greater than or equal to 1000 revolutions per minute (rpm), preferably greater than or equal to 2000 revolutions per minute and typically greater than or equal to 2500 revolutions per minute;

[0324] - the peripheral speed of the agitator is greater than or equal to 6 m / s, in particular greater than or equal to 8 m / s;

[0325] - the conversion of the second initial mixture into a C-glycoside ketone derivative goes from 80 100%.

[0326] 3.3) Vibrating crusher

[0327] A vibrating mill can be a vibro-mill (longitudinal movement having for example a frequency up to 30Hz) or a vibrating mill (three-dimensional figure-eight movement having a frequency up to 18 Hz).

[0328] A suitable vibratory grinder for the invention may, for example, correspond to that marketed by the company Retsch or Spex.

[0329] In general, the parameters of the synthesis process according to the invention are similar to those mentioned above for the planetary microbead mill.

[0330] 3.4) Extruder

[0331] An extruder suitable for carrying out the process according to the invention may be a single-screw or twin-screw extruder (co-rotating screws, counter-rotating screws, interpenetrating screws, or interpenetrating screws). As is known, a twin-screw extruder comprises two screws, generally parallel, rotating inside a barrel whose cross-section is figure-eight shaped.

[0332] By way of example, the Pharma 11 twin-screw extruder marketed by Thermo Fisher Scientific is suitable for carrying out the process according to the invention. In particular, it allows steps (B1) and (B2) according to the invention to be carried out in a sequential one-pot manner. This type of extruder also includes an inlet connected to a pump for introducing the starting reagents in solid form.

[0333] Fig. 3 illustrates a type of extruder enabling the continuous synthesis process of C-glycosides according to the invention to be carried out.

[0334] This figure illustrates a twin-screw extruder 100. As is known, the extruder 100 comprises two screws 103 that rotate inside a cylindrical barrel 106 by means of a drive unit 105. The barrel 106 is temperature-controlled by heating or cooling systems 107. The first starting reactant(s) can be introduced through the hopper 101 located at one end of the machine, generally near the drive unit 106, while the second starting reactant(s) can be introduced via a second hopper 102 connecting to the barrel in its middle. The final product resulting from this reaction or these reactions exits through the die 104.The feed nozzle 101 is thus suitable for introducing the first starting reagents in powder (solid) form / first initial mixture; likewise, the feed nozzle 102 is suitable for introducing the first starting reagents / first initial mixture also in solid form.

[0335] In order to introduce the starting reagents in liquid form, the extruder may include an inlet, located near nozzle 101 and / or nozzle 102, designed for this purpose. This inlet is connected to a pump and thus allows to introduce the liquid reagent(s) at a certain flow rate

[0336] To carry out the grinding step (Bl) of the process according to the invention, a first powder mixture comprising the sugar and the base is prepared and introduced via the feed nozzle 101. The extrusion process does not require the use of water as a liquid starting agent (LAG). The first starting reagent (liquid) is introduced via a pump into the inlet provided for this purpose. The first grinding takes place in the barrel.

[0337] The reaction parameters are the same as those presented above in paragraph 2°) synthesis process.

[0338] In particular, the rotation speed of the screw(s) is less than or equal to 1000 rpm and is generally between 10 rpm and 1000 rpm.

[0339] Alternatively, if the extruder does not include a second nozzle 102, it is possible to recover the C-glycoside ketone at the outlet of the barrel 106 and proceed with the grinding by introducing the C-glycoside-ketone via the nozzle 101 and the second starting reagent via the inlet provided for this purpose. 4) Usage

[0340] The invention also relates to the use of a first and / or a second mechanochemical reactor, to synthesize a C-glycoside, such as a C-glycoside ketone, a derivative of C-glycoside ketone, such as a C-glycoside-enone, or a C-glycoside imine.

[0341] Obviously all the characteristics described above for the synthesis process according to the invention apply to the present use and will not be reproduced below. EXAMPLES

[0342] The description of the tests below is given as a purely illustrative and non-limiting example.

[0343] Example 1: Synthesis in a planetary ball mill A) General Procedure

[0344] Al - Raw materials

[0345] For the tests, the starting raw materials are as follows:

[0346] [Tables 1] Compound Supplier Monosaccharide (hereinafter "S") D-glucose Merck Monosaccharide D-xylose Merck Base Sodium Hydroxide (NaOH) VWR Base Na2CO3 VWR First reagent Pentane-2,4-dione Merck Second reagent Benzaldehyde Acros Organics Amberlite® Resin (IR-120 H+) Acros Organics Mineral acid NaHSO4 Merck Mineral acid HCl Acros Organics

[0347] A2 - Planetary mechanosynthesis mill

[0348] For this Example 1, a planetary mechanosynthesis mill was used. In particular, the mill is the Fritsch PULVERISETTE 7 premium line (P7PL) planetary mill. Two 20 mL stainless steel bowls, each containing 80 stainless steel balls 5 mm in diameter, allow two reactions to be carried out in parallel. A counterweight is placed in the mill when using only one bowl. The millings are performed in five-minute cycles with a one-minute pause between each cycle, at a rotational speed of 500 rpm in reverse mode. The platter and the reactors do not rotate in the same direction; the rotation causes the balls to impact the walls of the bowls.

[0349] A small amount of liquid (hereinafter referred to as LAG), on the order of 0.4 mL of water, is added to improve reactivity (not considered as a solvent).

[0350] A3 - Synthesis process using the PULVERISETTE 7 mill

[0351] Synthesis of C-glycoside ketone

[0352] The monosaccharide (1 eq.) and the base (1.2 or 1.5 eq.) are placed in a 20 mL stainless steel bowl containing 80 stainless steel balls, 5 mm in diameter. Pentane-2,4-dione is added, along with LAG (H2O; ΔT (LAG factor = 0.2)). The reaction time in the P7PL planetary mill varies depending on the monosaccharide (see Table 2). The product in paste form is recovered by solubi- The solution is placed in H2O inside the bowl, neutralized (pH=5) with an Amberlite resin (IR-120 H+), and then evaporated. The crude reaction product is analyzed by NMR.

[0353] The reaction is carried out without external heating.

[0354] Synthesis of C-glycoside enone

[0355] The synthesis of C-glycoside-enone is carried out in two successive steps ("one-pot two-step"), without removing the intermediate product from the mill. The first reaction is identical to that described above. The second reaction consists of adding benzaldehyde to the reactor once the first reaction is complete, and optionally a base. The residence time is 12 cycles of 5 minutes with a rest time of 1 minute between each cycle (i.e., 71 minutes).

[0356] Similarly, the reaction is carried out without external heating. The final product is then neutralized. B) Experimental conditions and results

[0357] B1 -C-glycoside ketone synthesis

[0358] [Table 2]: Experimental conditions Example: Starting "S" Quantity of starting "S" (g) Base NaOH (eq.) Reagent (eq.) Residence time (min.) LAG pL / mg Step Neutralization pH Example 1 D-glucose 1 1.5 eq. 1 eq. 32x5 0.2 NaHSO4 in a grinder (3x5 min) Example 2 D-xylose 1 1.5 eq. 1 eq. 24x5 0.2 Amberlite® Resin Example 3 D-glucose 1 1.5 eq. 1 eq. 40x5 0.2 Amberlite® Resin Example 7

[0359] [Table 3]: Results Example: Estimated conversion EX.1 86% EX.2 100% EX.3 78%

[0360] Thus, a process in a planetary mill allows the synthesis of C-glucoside ketone. A 100% conversion is obtained from the monosaccharide D-xylose after 143 minutes (24 cycles / 5-minute milling including a 1-minute pause between each cycle).

[0361] B2 - Synthesis of C-glycoside-enone according to the process of the invention using the planetary mill

[0362] [Table 4]: Experimental conditions (first stage) Example: Starting "S" Quantity of starting "S" (g) Base NaOH (eq.) Reagent (eq.) Reaction time (min.) LAG pL / mg Ex.4 D-glucose 1 1.2 eq. 1 eq. 32 x 5 = 175 0.2 Ex.5 D-xylose 1 1.5 eq. 1 eq. 24 x 5 = 120 0.2 Ex.6 D-glucose 1 1.2 eq. 1 eq. 32 x 5 = 175 Concentration 450g / L Ex.7 D-xylose 1 1.2 eq. 1 eq. 32 x 5 = 175 Concentration 450g / L

[0363] [Table 5]: Experimental conditions (2nd stage) Example 2nd reagent (eq.) Residence time (min.) Temperature Step Neutralization pH Example 4 1 eq. (12x5) + 11 = 71 Without heating - - Example 5 1 eq. (12x5) + 11 = 71 Without heating Amberlite® 7 Resin Example 6 1 eq. (12x5) + 11 = 71 Without heating Amberlite® 7 Resin Example 7 1 eq. (12x5) + 11 = 71 Without heating Amberlite® 7 Resin

[0364] [Table 6]: Results Ex. Mass spectrometry m / z Ex.4 [M+Na] 331: C-glucoside-enone Ex.5 [M+Na] 301: C-xyloside-enone Ex.6 [M+Na] 243: C-glucoside ketone intermediate [M+Na] 331: C-glucoside-enone Ex.7 [M+Na] 301: C-xyloside-enone

[0365] The process according to the invention in a planetary mill allows the C-glycoside-enone to be formed continuously (12 cycles / millings of 5 minutes). In particular, it allows the C-glycoside-enone to be formed without removing the C-glycoside ketone formed at the end of step 1 from the mill (i.e., without an intermediate neutralization step).

[0366] Example 2: Synthesis in a three-dimensional mill in LAG mode A) General Procedure

[0367] Al - Raw materials

[0368] For the tests, the starting raw materials are as follows:

[0369] [Tables?] Supplier Compound Monosaccharide (hereinafter "S") D-glucose Merck Base Sodium Hydroxide (NaOH) VWR Base Na2CO3 VWR First Reagent Pentane-2,4-dione Merck Mineral Acid HCl VWR

[0370] A2 - Three-dimensional wet-phase microbead mill

[0371] For this example 2, a Dynomill ECM AP-05 three-dimensional micro-bead mill from Willy A. Bachofen AG (WAB) was used. This mill contains 1.235 kg of micro-beads and has been adapted to include a heating device. Thus, the mill includes a heating device positioned at the inlet of the stationary chamber, and the first mixing element acts as a susceptor (document WO 2019 / 228983).

[0372] In particular, the heating device has the following characteristics:

[0373] [Tables8] Characteristic Components Generator 10kW power generator with a frequency ranging from 17 to 200 kHz / series generator IDPartner reference 1X3600 model PO8010. Inductor Multi-strand, resin-coated Litz wires for easy removal. IDPartner 300-strand Litz Cu 9.425 mm² 6x50x0.2mm cable. Susceptor Mixing element as described in US document 5 597 126 (fig. 4) in Phyterm® 260 stainless steel, equivalent to ArcelorMittal Kara ferric stainless steel, grade K44. Magnetic screen Cylindrical toroid in Fluxtrol®. Current supply The rod 11 has been modified to integrate the 3mm² copper coaxial current supply. This coaxial cable alters the rod's center of gravity; it is balanced by compensating with tungsten screws. Type K thermocouples at the inlet and outlet of the grinding chamber. Rotary copper contactor.

[0374] The microbeads are made of zirconium oxide and have a diameter of 0.5 mm and are marketed in particular under the brand name Zirmil® Y Ceramic Beads by the company Saint-Gobain.

[0375] The grinding chamber of the mill has a capacity of 514 mL and is filled, in volume, relative to its total volume and depending on the tests, with 167 or 334 mL of the microbeads described above.

[0376] During operation, the microbeads are agitated by an agitator at a rotational speed that can vary from 0.01 to 16 m / s. The agitator also includes chrome cast iron mixing discs.

[0377] A3 - Process for the synthesis of C-glycoside ketone using the three-dimensional wet-phase mill

[0378] A first initial mixture comprising the monosaccharide, the base, the first reagent and water are pre-mixed vigorously by magnetic stirring at 25°C in a tank (the experimental conditions are illustrated in the table below). below).

[0379] The first mixture is pumped using a peristaltic pump at a flow rate of 200 mL / min and the stream is introduced into the Dynomill ECM AP-05 three-dimensional mill described above. The agitator rotates at 10 m / s. In particular, the heating device 20 heats the grinding chamber to a temperature of 90°C. The mill operates continuously (the product exiting through outlet 6 is reintroduced into inlet 5 of the grinding chamber).

[0380] The final product is then neutralized.

[0381] After a certain time in the grinder, the reaction medium is analyzed by NMR spectroscopy and mass spectrometry. B) Experimental conditions and results

[0382] [Table 9]: Experimental conditions Ex. Starting “S” Quantity of starting “S” (g) Conc. in “S” Base (eq.) Jer reagent (eq.) Residence time (min.) Step Neutralization pH Ex.8 D-glucos e 450 900 g / L 5 mol / L NaHCO3 / 1.5 eq. 1.2 eq. 180 HCl 1 Ex.9 D-glucos e 450 900 g / L 5 mol / L Na2CO3 / 1.5 eq. 1.2 eq. 180 HCl 1 Ex.10 D-glucos e 101 450 g / L 2.5 mol / L NaHCO3 / 1.5 eq. 1 eq. 80 HCl 5 Ex.ll D-xylose 150 150 g / L 1 mol / L NaOH 1.2 eq. 1 eq. 1 min HCl 7

[0383] [Table 10]: Results Example: Product formed Estimated conversion Ex. 8 Yes 100% Ex. 9 Yes 100% Ex. 10 Yes 88% Ex. 11 Yes 64%

[0384] Thus, the synthesis process according to the invention using a three-dimensional microbead mill allows the continuous production of a C-glycoside ketone with a conversion ranging from 88 to 100%.

[0385] Example 3: Synthesis of C-glycoside-ketone in an extruder ([Fig.4] and 5)

[0386] For this embodiment example, a pharma 11 twin-screw extruder (Thermo Fisher Scientific) was used.

[0387] D-glucose (50 g, eq) is ground with NaOH (12.11 g, 1.1 eq) in a mortar. The powder mixture is fed into the extruder via a feeder at a rate of 1 g / min. The first starting reagent, penta-2,4-dione (25.264 g, 1 eq), is added via an HPLC pump at a rate of 0.4 g / min. The synthesis is carried out at room temperature (no external heating or heating input).

[0388] The rotation speed of the twin screw is 80 rpm.

[0389] The stay time is 20 minutes.

[0390] Samples were taken from the screw outlet and TLC, MS and NMR analyses showed the presence of the expected C-glucoside as well as unreacted glucose. The reference example corresponds to example 3 (Table 2) described above.

[0391] As examples 1 to 3 above illustrate, the method according to the invention thus makes it possible to: synthesize C-glycosides with or without solvent, in shorter times and / or at lower temperatures than the literature, and continuously, perform multiple "one pot sequential" syntheses allowing the functionalization of C-glycosides in the same reactor, without intermediate purification steps.

Claims

Demands

1. A process for the synthesis of at least one C-glycoside comprising the following successive steps: (A) introducing into a first mechanochemical reactor, separately or previously mixed, at least one sugar in the form of pyranose and / or furanose and of the D and / or L series, said sugar having at least one hydroxyl function at the obligatorily free anomeric position, a first starting reagent which is a [3-diketone and a base, in order to form a first initial mixture; (B1) at least a first grinding of said first initial mixture at a temperature greater than or equal to 20°C in said first mechanochemical reactor, for a residence time less than or equal to 6 hours, so as to form a ketone C-glycoside; (C) recovering from the outlet of the first mechanochemical reactor a final product comprising said at least C-glycoside.

2. A synthesis process according to claim 1, wherein said first initial mixture comprises water as LAG.

3. Synthesis process according to claim 1, wherein said at least first grinding of said initial first mixture is carried out at a temperature ranging from 30°C to 120°C, and in particular at a temperature ranging from 40°C to 90°C.

4. Synthesis process according to claim 1 or 2, wherein the residence time of said first initial mixture within said first mechanochemical reactor is less than or equal to 4 hours and in particular ranging from 1 minute to 3 hours.

5. A synthesis process according to any one of the preceding claims, wherein said at least one sugar is selected from: a monosaccharide, an oligosaccharide having from 2 to 10 sugar units or a polysaccharide having more than 11 sugar units and a mixture thereof.

6. A synthesis process according to claim 5, wherein said monosaccharide is selected from D-glucose, D-galactose, D-mannose, D-xylose, D-lyxose, L-fucose, L-arabinose, D-ribose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D-iduronic acid or L-iduronic acid, A-acetyl-D-glucosamine, A-acetyl-D-galactosamine and advantageously designates D-glucose, D-xylose, A-acetyl-D-glucosamine or L-fructose, and most preferably D-xylose; or said oligosaccharide is selected from oligosaccharides containing up to 6 sugar units, such as D-maltose, D-lactose, D-cellobiose, D-melibiose, D-maltotriose, a disaccharide combining a uronic acid selected from D- or L-iduronic acid or D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, A-acetyl-D-galactosamine, N-acetyl-D-glucosamine, an oligosaccharide containing at least one xylose advantageously selected from xylobiose, methyl-[3-xylobioside, xylotriose, xylotetraose, xylopentaose and xylohexaose and preferably xylobiose which is composed of two xylose molecules linked by a beta-1-4 bond, or said polysaccharide is selected from cellulose, starch, amylose, amylopectin, galacturonan, glucuronan, chitin, chitosan, dextran, glucans, mannans, galactans, alginates, pectins, pullulan or a mixture thereof;and one of their mixtures.

7. A synthetic process according to any one of the preceding claims, wherein said first starting reagent, which is a [3-diketone], corresponds to the following formula (I): [Chem. 3] R^CO-CH^-CaR® (formula I). ​​in which R1 and R2, independently of each other, represent a linear or branched alkyl, hydrofluoroalkyl, saturated or unsaturated chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl ring, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said ring or said radical being optionally interrupted by one or more heteroatoms selected from oxygen, sulfur, nitrogen, preferably R1 represents an alkyl group, such as a methyl group.

8. A synthesis process according to any one of the preceding claims, wherein in step (A), the concentration of said at least one sugar in said initial first mixture is greater than or equal to 100 g / L, preferably from 100 to 10,000 g / L, in particular from 200 g / L to 3,000 g / L and typically from 450 g / L to 2,800 g / L.

9. A synthesis process according to any one of the preceding claims. preceding, wherein in step (A), the quantity of said first starting reagent, for one equivalent (eq.) of said at least one sugar, varies from 0.75 to 5 eq., preferably varies from 1 to 2 eq. and typically varies from 1 to 1.2 eq.

10. A synthesis process according to any one of the preceding claims, wherein in step (A), the basic quantity for one equivalent (eq.) of said at least one sugar varies from 1 to 4 eq., preferably varies from 1.2 to 3 eq and typically varies from 1.2 to 2.5 eq.

11. A synthesis process according to any one of the preceding claims, comprising at least: (B2) a second grinding carried out in said first mechanochemical reactor after step (B1) or carried out in a second mechanochemical reactor, different from the first mechanochemical reactor after step (C), from a second initial mixture comprising at least said C-glycoside ketone previously formed at the end of step (B1), said starting C-glycoside ketone and a second starting reagent, so as to functionalize said starting C-glycoside ketone and obtain another C-glycoside.

12. Synthesis process according to claim 11, wherein said second grinding (B2) is carried out directly after step (B1) and in said first mechanochemical reactor.

13. A synthetic process according to claim 11 or 12, wherein said functionalization reaction is selected from: - an aldol-crotonization reaction, so as to obtain a C-glycoside having an unsaturated α[3] ketone function, such as a C-glycoside-enone, - an addition reaction of O-, N-, S-, C-nucleophiles, preferably aliphatic or aromatic A-nucleophiles, in order to obtain a C-glycoside imine.

14. A method according to any one of claims 11 to 13, wherein in step (B2), said second starting reagent is selected from: - a compound of formula (II) [Chem. 4] formulated u.\B in which R3 is chosen from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R3 is a hydrogen atom and R4 is chosen from the group consisting of: -CHO, CH2 NH2, preferably, said second starting reagent is chosen from: benzaldehyde or benzylamine; and / or * a compound of formula (III) [Chem. 5] R '-C HO (Formed? § 1) in which R5 is chosen from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms.

15. A synthesis process according to any one of the preceding claims, comprising a step (D) of neutralizing the final product.

16. A method according to any one of claims 1 to 14, characterized in that said first or second mechanochemical reactor is selected from: a planetary ball mill; a vibrating mill; a three-dimensional wet phase mill with or without balls or an extruder.

17. Use of a first and / or a second mechanochemical reactor, for the implementation of a process for the synthesis of at least one C-glycoside according to any one of claims 1 to 16.

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