Method for synthesising a c-glycoside

Abstract

The present invention relates to a method for synthesising at least one C-glycoside, the method comprising the following steps, in succession: (A) introducing, separately or mixed beforehand, at least one sugar in D- and / or L- pyranose and / or furanose form, the sugar having at least one hydroxyl function at the anomeric position which is compulsorily free, a first reagent which is a β-diketone, and a base into a first mechanochemical reactor, in order to form a first initial mixture; (B1) at least grinding, for a first time, the first initial mixture at a temperature of greater than or equal to 20°C in the first mechanochemical reactor for a residence time of less than or equal to 6 hours, so as to form a C-glycoside ketone; (C) recovering a final mixture at the outlet of the first mechanochemical reactor. The present invention also relates to the use of the mechanochemical reactor to synthesise a C-glycoside or a C-glycoside derivative comprising the at least one C-glycoside.

Description

[0001] Process for the synthesis of a C-glycoside

[0002] TECHNICAL FIELD TO WHICH THE INVENTION RELATES

[0003] The present invention relates to a method for synthesizing C-glycosides which may comprise a ketone function or chemical functional group.

[0004] In particular, the present invention relates to a process for the synthesis of C-glycosides which may comprise at least one ketone function or at least one other chemical functional group, carried out by mixing / grinding (i.e.: grinding, microgrinding or even extrusion) generally in a single specific mechanochemical reactor, such as for example a three-dimensional wet phase mill.

[0005] The present invention also refers to the use of this mechanochemistry reactor to synthesize during one and generally several sequential reactions, at least one C-glycoside, without it being necessary to remove the reaction medium(s) from the mechanochemistry reactor.

[0006] TECHNOLOGICAL BACKGROUND

[0007] Carbohydrates, also called carbohydrates with general formula C n (H2O) n, are a family of abundant natural compounds found in different forms: monomers, oligomers and polymers. This bioresource is the subject of intense research due to the numerous fields of application of its derivatives, including in particular C-glycosides. For example, the molecule CpD-xylopyranoside-2-(S)-hydroxypropane (Pro-Xylane®) developed by the company L'OREAL is a C-glycoside derivative prepared from D-xylose and is recognized as an anti-aging molecule stimulating the biosynthesis of glycosaminoglycans of interest.

[0008] C-glycosides are a class of compounds in which a carbohydrate is linked to an aglycone or other 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.

[0009] Several methodologies have been developed for the preparation of C-glycosides.

[0010] Most of the preparation of such compounds often involves multi-step reactions that require the protection of the sugar hydroxyl groups and the activation of the anomeric position by the introduction of an appropriate activatable group or by oxidation. These transformations consume large quantities of reagents as well as organic solvents, impacting in particular the E factor (i.e.: mass ratio of waste to desired product). Indeed, in general, the synthesis is carried out conventionally in H2O-organic solvent medium (such as methanol MeOH, tetrahydrofuran THF, dimethylformamide DM F, acetonitrile CH3CN, dimethylsulfoxide DMSO, ethanol EtOH) by reaction of a protected monosaccharide (monosaccharide) with pentane-2,4-dione (i.e.: acetylacetone) present in excess (molar ratio ose / acetylacetone = 1 / 2) with a base, also present in excess in the reaction medium (molar ratio ose / 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, G., Enantio selective Synthesis of Pseudomonic Acids. I. Synthesis of Key Intermediates, Helvetica Chimica Acta 1982, 65 (7), 2333 - 2337 or Howard, S.; Withers, S.G., Bromoketone C-glycosides, a new class of beta-glucanase inactivators J. Am. Chem. Soc. 1998, 120, 10326-10331).

[0011] The conventional synthesis of C-glycosides described above thus has certain disadvantages. It is carried out in batch mode and not continuously, complex to implement, long and not very environmentally friendly. In particular, the two publications mentioned above describe multi-step syntheses including protection / deprotection reactions of the hydroxyls of sugars to access C-glycoside derivatives, and the use of either drastic conditions and / or toxic reagents. Schoenenberger et al, first describe the protection of D-ribose in acetal form which then undergoes a Wittig reaction at reflux in acetonitrile, the intermediate acyclic derivative is then treated with MeONa to lead to a mixture of acetylated or non-acetylated C-riboside.Howard et al. use a tetrabenzylated allyl-pC-glucoside as the starting substrate, which undergoes epoxidation by mCPBA followed by reduction by DI BAL-H and finally a Jones oxidation with chromic acid. The pC-glucoside of interest is finally obtained after deprotection of the benzyl groups. These syntheses are not eco-compatible.

[0012] The publication of 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 / ?-DC-glycosides ketone by Knoevenagel condensation from pentane-2,4-dione with an unprotected ose, no longer in an organic solvent, but in an aqueous alkaline medium.

[0013] The synthesis reaction according to Lubineau et al. is illustrated in Fig. 1.

[0014] The Knoevenagel condensation of pentane-2,4-dione with ose allows the formation of the intermediate compound named 11 in Figure 1 above by a nucleophilic addition of the anion of the pentane-2,4-dione formed in situ onto the aldehyde of the ose, which is followed by a p-elimination of water to form the enone compound 12. This intermediate 12 then gives rise to an intramolecular Michael addition leading to the cyclization of the intermediate C-glycoside 14, most likely as a mixture of the four possible stereoisomers: a,p-furanosides and a,p-pyranosides (since when the reaction is carried out at room temperature, a mixture of the four isomers 15a,b,c,d in which the pC-pyranoside 15d predominates, is obtained by retro-Claisen aldolization with concomitant elimination of sodium acetate). Basic catalysis almost exclusively results in the formation of the thermodynamic stereoisomer P-glucopyranoside 15d.This process, however, has the disadvantage of being carried out in the laboratory in conventional glassware in batch mode. It is therefore less suitable for industrially producing a pDC-glycoside ketone. The time required to carry out the synthesis is generally 6 to 12 hours in water at a temperature around 90°C.

[0015] From this publication, a valorization of C-glycosides was undertaken, notably by the company L'OREAL to obtain Pro-Xylane® and many other compounds. Patent FR 2 818 547 also filed in 2000 describes in particular a process for manufacturing C-glycoside derivatives which may have the following formula (I'): in which

[0016] S is a monosaccharide or a polysaccharide; the S-CH2-X bond represents a C-anomeric bond;

[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 consisting of water and an organic solvent miscible in water, preferably a polar protic solvent and advantageously tetrahydrofuran, dioxane, / V-methyl-pyrrolidine, dimethylformamide, acetonitrile, and / or alcohols in particular ethanol, 1 equivalent of a monosaccharide or a polysaccharide of formula S,

[0021] - to add between 1 and 2 equivalents of a p-diketonic compound of general formula:

[0022] R”-CO-CH2-CO-R, with R as defined previously and R" corresponding to the definition given previously for R, with the exception of hydrogen (acetylacetone being already described in the publication by Lubineau), 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, washing the reaction medium with an organic solvent which may be chosen from ethyl acetate, dichloromethane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, methyl ethyl ketone,

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

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

[0026] - to dry the product obtained under vacuum, then possibly to purify it by chromatography and / or crystallization. The publication of 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 unprotected 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 1h30 depending on the starting sugar, but this synthesis requires an EtOH / H2O mixture 4:1) to achieve a yield of 98% in 1 h.

[0027] The publication by Rodriguez et al. “A convenient, one-step synthesis of beta-C-glycosidic ketones in aqueous media”, Chemical communications, Royal Society of Chemistry, UK, 2000, pages 2049-2050, describes the synthesis of pC-glycoside ketones from unprotected carbohydrates in aqueous alkaline media via the Knoevenagel condensation. The synthesis of pC-glucopyranoside from D-Glucose shows a yield of 96% for a relatively long reaction time of 6 h at 90°C and at a low sugar concentration of 45 g / mol or 0.25 mol / L.

[0028] The publication by Yang You et al. “Recent Advances in the Chemical Synthesis of C-Glycosides”, Chemical Reviews, vol.117, no.19, 2017 summarizes the progress in the synthesis of C-pyranosides / furanosides covering the literature from 2000 to 2016. In particular, Scheme 94 (page 12319) shows that it is necessary to use a solvent and / or high temperatures, with reaction times that are long.

[0029] Finally, the publication of Riafrecha Leonardo et al. “Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer-associated carbonic anhydrase isoforms IX and XII”, Biologic & Medicinal Chemistry, Elsevier, vol. 22, no. 19, 2014, describes a new class of C-glycosides incorporating the methoxyaryl moiety, which was designed to selectively target and inhibit the extracellular domains of cancer-relevant carbonic anhydrase isozymes. C-glycoside enones were prepared by aldol condensation reaction of C-glycosyl ketones with appropriate aromatic aldehydes. In particular, this paper describes the synthesis of C-glycoside enones obtained in four successive steps (C-glycosylation, acetylation, aldolization, and then deacetylation) requiring chromatography column purifications, consumption of organic solvents, and time.

[0030] As illustrated above, the synthesis of C-glycosides and in particular of C-glycosides linked to an aglycone presenting a functional group of interest (i.e.: hereinafter referred to as C-glycoside derivatives) has evolved little since 2011. A synthesis process that is easy to implement and allows selective modification of oses (i.e.: sugars) thus remains a real challenge.

[0031] There is thus a need in the state of the art to provide a new process for the synthesis of C-glycosides and their derivatives which at least partially avoids the aforementioned drawbacks.

[0032] In particular, there is a need in the state of the art to provide a process for the synthesis of C-glycosides, as well as their derivatives, preferably in continuous mode, which is simple, industrially exploitable, in particular not requiring too long a reaction time (namely a reaction time shorter than conventional processes which varies from 6 to 48 hours). SUBJECT OF THE INVENTION

[0033] To this end, the subject of the present invention is a process for the synthesis of at least one C-glycoside comprising the following successive steps:

[0034] (A) the introduction into a first mechanochemical reactor, separately or previously mixed, of at least one sugar in pyranose and / or furanose form and of D and / or L series, said sugar having at least one hydroxyl function in the anomeric position which is necessarily free, of a first reagent which is a p-diketone and of a base, in order to form a first initial mixture;

[0035] (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 C-glycoside ketone;

[0036] (C) recovery at the outlet of the first mechanochemistry reactor of a final mixture.

[0037] Other non-limiting and advantageous characteristics of the method according to the invention, taken individually or in all technically possible combinations, are the following:

[0038] - said first initial mixture comprises water as LAG;

[0039] - said at least first grinding of said first initial 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;

[0040] - the residence time of said first initial mixture within said first mechanochemical reactor is less than or equal to 4 hours and in particular ranges from 1 minute to 3 hours;

[0041] - said at least one sugar is chosen from: a monosaccharide, an oligosaccharide having from 2 to 10 sugar units or a polysaccharide having more than 11 sugar units (such as from 11 to 20 or more sugar units), and a mixture thereof;

[0042] - said monosaccharide is chosen from D-galactose, D-mannose, D-xylose, D-lyxose, D-ribose, L-fucose, L-arabinose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D- or L-iduronic acid, / V-acetyl-D-glucosamine, / V-acetyl-D-galactosamine and advantageously denotes D-glucose, D-xylose, / V-acetyl-D-glucosamine or L-fucose, and very preferably D-xylose or one of their mixtures;or said oligosaccharide is chosen 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 chosen from D- or L-iduronic acid or D-glucuronic acid with a hexosamine chosen from D-galactosamine, D-glucosamine, / V-acetyl-D-galactosamine, / V-acetyl-D-glucosamine, an oligosaccharide containing at least one xylose advantageously chosen from xylobiose, methyl-p-xylobioside, xylotriose, xylotetraose, xylopentaose and xylohexaose and preferentially xylobiose which is composed of two xylose molecules linked by a beta-1,4 bond, or said polysaccharide is chosen 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;

[0043] - said first reagent which is a p-diketone corresponds to the following formula (I):

[0044] R 1 -CO-CH2-CO-R 2 (formula I), in which

[0045] R 1 and R 2 , represent independently of one another, a linear or branched, saturated or unsaturated alkyl, hydrofluoroalkyl chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl cycle, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said cycle or said radical possibly being interrupted by one or more heteroatoms chosen from oxygen, sulfur, nitrogen, preferably R 1 represents an alkyl group, such as a methyl group;

[0046] - 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 ranging from 100 g / L to 10,000 g / L, in particular ranging from 200 g / L to 3000 g / L and typically ranging from 450 g / L to 2800 g / L, such as for example 2600 g / L;

[0047] - during step (A), the quantity of said first 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.;

[0048] - during step (A), the base 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.;

[0049] - said method comprises 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), called starting C-glycoside ketone and a second starting reagent, so as to functionalize said starting C-glycoside ketone and obtain another C-glycoside;

[0050] - said second grinding (B2) is carried out directly after step (B1) and in said first mechanochemistry reactor;

[0051] - said functionalization reaction is chosen from:

[0052] * an aldolization-crotonization reaction, so as to obtain a C-glycoside having an unsaturated a,p ketone function, like a C-glycoside-enone,

[0053] * an addition reaction of O-, A / -, S-, C-nucleophiles, preferably of / V- aliphatic or aromatic nucleophile, in order to obtain a C-glycoside imine;

[0054] - during step (B2), said second starting reagent is chosen from: * a compound of formula (II)

[0055] R 4 Formula (II) in which R 3 is selected from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R 3 is a hydrogen atom and R 4 is selected from the group consisting of: -CHO, CH2NH2; preferably, said second starting reagent is selected from: benzaldehyde or benzylamine; and / or

[0056] * a compound of formula (III)

[0057] R 5 -CHO (Formula III) in which R 5 is chosen from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms;

[0058] - said method comprises a step (D) of neutralization of the final product;

[0059] - said first or second mechanochemical reactor is chosen from:

[0060] * a planetary ball mill,

[0061] * a vibrating crusher

[0062] (ie: vibrating grinder or vibration grinder);

[0063] * a three-dimensional wet phase mill with or without balls;

[0064] * an extruder.

[0065] The present invention also relates to the use of a first and / or a second mechanochemical reactor, for synthesizing a C-glycoside, such as a C-glycoside ketone, a C-glycoside ketone derivative (generally derived from the starting C-glycoside ketone), such as a C-glycoside enone, or a C-glycoside imine.

[0066] Of course, the various features, variations and embodiments of the invention may be combined with each other in various combinations to the extent that they are not incompatible or mutually exclusive.

[0067] DESCRIPTION OF FIGURES

[0068] In addition, various other characteristics of the invention emerge from the appended description given with reference to the drawings which illustrate non-limiting embodiments of the invention and where:

[0069] [Fig. 1] represents the synthesis reaction of ketone C-glycosides according to a prior art method, the publication of Lubineau et al, in 2000; [Fig. 2] represents a sectional view, along a sectional plane passing through the longitudinal axis XX, of an embodiment of the invention in which the mechanochemistry reactor is a three-dimensional wet-phase mill;

[0070] [Fig. 3] represents another embodiment of the invention in which the mechanochemical reactor is a co-rotating twin-screw extruder with double raw material inlets;

[0071] [Fig. 4] represents the mass spectrum of the sample obtained according to another embodiment of the synthesis method according to the invention in which the first mechanochemical reactor is chosen from a co-rotating twin-screw extruder; and

[0072] [Fig. 5] (a) represents the NMR spectrum 13 C of the example according to the invention obtained in a planetary mill (example 3, Table 2) and (b) represents the NMR spectrum 13 C of the sample in Fig.4.

[0073] It should be noted that, in these figures, the structural and / or functional elements common to the different variants may have the same references.

[0074] DETAILED DESCRIPTION OF AN EXAMPLE OF IMPLEMENTATION

[0075] 1°) Definitions

[0076] In the present invention, unless otherwise specified, the term "comprising" and its derivatives should be understood as non-limiting and not excluding the presence of other components or steps. In certain particular embodiments, the term "comprising" may be understood as "consisting essentially of" or "consisting of".

[0077] 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 CC bond instead of the usual C-O glycosidic bond.

[0078] According to the invention, by "C-glycoside ketone" is meant the C-glycoside formed from step (B1) 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 cycle (i.e.: monosaccharide, oligosaccharide or polysaccharide). In particular, the ketone function is in position 2 of the propyl chain (aglycone) linked to the anomeric carbon of the sugar in position a or p.

[0079] “By a C-glycoside ketone derivative” or by “C-glycoside of interest”, is meant 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 / V-nucleophilic group in order to obtain a C-glycoside-imine.

[0080] Hereinafter, "LAG" (Liquid-assisted grinding) is a liquid additive characterized by a q value that must be between 0 (not included) and 2, q being defined by the ratio of liquid additive in iL to the sum of the reactants in mg. LAG corresponds to a small quantity of liquid (usually water) which typically allows the progress of synthesis reactions to be accelerated.

[0081] 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 as including the values ​​X and Y.

[0082] 2°) Synthesis process

[0083] The Applicant has focused on the development of a new process for the synthesis of C-glycoside and in particular of a C-glycoside ketone or one of its derivatives (i.e.: a C-glycoside ketone functionalized by another chemical functional group).

[0084] As mentioned above, the method according to the invention refers to a method for synthesizing at least one C-glycoside comprising the following successive steps:

[0085] (A) the introduction into a first mechanochemical reactor, separately or previously mixed, of at least one sugar in pyranose and / or furanose form and of D and / or L series, said sugar having at least one hydroxyl function in the anomeric position which must be free, of a first starting reagent which is a p-diketone and of a base, in order to form a first initial mixture;

[0086] (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 C-glycoside ketone;

[0087] (C) recovery at the outlet of the first mechanochemistry reactor of a final mixture.

[0088] The Applicant has thus developed a process which, surprisingly and unexpectedly, allows the synthesis of C-glycoside and in particular of a ketone C-glycoside at the end of step (B1). As will be described below, the process according to the invention also makes it possible to synthesize other C-glycosides of interest, namely functionalized C-glycosides obtained from the ketone C-glycoside, by simply adding another starting reagent to the same mechanochemistry reactor directly after having carried out step (B1) (i.e.: obtained in sequential “one pot”). Indeed, the use of a mechanochemistry reactor which allows continuous syntheses to be carried out, such as a planetary mill, a three-dimensional wet phase mill (with or without grinding balls) or even an extruder allows the synthesis of the C-glycoside of interest (i.e.: functionalized C-glycoside) in “one pot”.

[0089] Furthermore, the synthesis process according to the invention has the advantage of being carried out without the use of solvent with only the use of a base and advantageously (but not necessarily) also in the presence of water as LAG in particular when the mechanochemistry 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 the processes according to the prior art, the use of organic solvent, such as methanol, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide or even ethanol.

[0090] In addition, the quantities of reaction agents, such as the first starting reagent p-diketone, the base and where appropriate the second starting reagent, are relatively small (for example, of the order, for one equivalent of sugar, of 0.75 to 5 equivalents of the first starting reagent or even of 1 to 4 equivalents of base).

[0091] Furthermore, the synthesis of 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 of Lubineau or 1 hour to 1 hour 30 under microwave irradiation described in the publication of Feng et al.).

[0092] The process according to the invention also has the advantage (depending on the choice of the mechanochemistry reactor used) of carrying out C-glycoside mechanosynthesis in continuous flow. It is thus possible to have a high sugar concentration (i.e.: monosaccharide, oligosaccharide or polysaccharide). Indeed, a reactor of the type: three-dimensional wet phase mill or extruder allows the synthesis of C-glycoside continuously, unlike the planetary or vibrating ball mill which operate in batch production.

[0093] When the process comprises 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).

[0094] The Applicant has further observed, and as the experimental tests below prove, that the conversions into C-glycoside ketone or into another C-glycoside of interest, such as a C-glycoside enone, were very high, at least 70%, in particular at least 85%, or even greater than or equal to 99% (depending on the experimental conditions). Thus, no or few by-products are formed during the synthesis process according to the invention, in particular at the end of step (B1) and / or at the end of step (B2).

[0095] In addition, the method 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, where appropriate the choice of the second starting reagent (determined depending on the functionalization chosen) and this in sequential "one-pot", namely it is possible to use the same mechanochemistry reactor operating in batch mode (planetary mill, vibrating mill) or in continuous mode (three-dimensional wet phase mill - with or without grinding balls - or even extruder). Of course, other functional reactions in one-pot can be carried out after step (B2) (grinding step (B3), etc.) depending on the desired C-glycoside of interest.The method according to the invention also has the advantages of having a lower cost price (the raw materials used are in fact widely available, non-polluting and inexpensive) and of having excellent reproducibility. As mentioned above, the method according to the invention also has the advantage, according to certain embodiments, of being able to be implemented continuously. However, these characteristics are important for application on an industrial scale.

[0096] Finally, despite the numerous researches conducted on the synthesis of C-glycosides (C- ketone glycosides or its derivatives), none has suggested the aforementioned process and in particular at least one grinding step in a mechanochemistry reactor from the starting reagents.

[0097] 2.1) Step (A)

[0098] As mentioned above, the process for synthesizing C-glycoside according to the invention begins with a step (A) of introducing into a first mechanochemical reactor, separately or previously mixed, at least:

[0099] - a sugar in pyranose and / or furanose form and of D and / or L series,

[0100] - a first starting reagent which is a p-diketone,

[0101] - and where appropriate a base and water as LAG when said first mechanochemical reactor is chosen from a mill and in particular a three-dimensional wet phase mill.

[0102] All of these constituents form a mixture, hereinafter called the “first initial mixture”.

[0103] In particular, the sugar has at least one hydroxyl function at the anomeric position which must be free. It can be chosen 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.

[0104] 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, / V-acetyl-D-glucosamine, / V-acetyl-D-galactosamine and a mixture thereof. Advantageously, the monosaccharide is selected from D-glucose, D-xylose, / V-acetyl-D-glucosamine or L-fructose, and is typically D-xylose.

[0105] In particular, the oligosaccharide may be chosen from oligosaccharides containing up to 6 sugar units. For example, such an oligosaccharide may be chosen from: D-maltose, D-lactose, D-cellobiose, D-maltotriose, D-melibiose, a disaccharide combining a uronic acid chosen from D- or L-iduronic acid or D-glucuronic acid with a hexosamine chosen from D-galactosamine, D-glucosamine, / V-acetyl-D-galactosamine, / V-acetyl-D-glucosamine, an oligosaccharide containing at least one xylose advantageously chosen from xylobiose, methyl-p-xylobioside, xylotriose, xylotetraose, xylopentaose and xylohexaose. The oligosaccharide can be chosen in particular from xylobiose which is composed of two xylose molecules linked by a beta-1-4 bond.

[0106] According to the invention, the polysaccharide may be chosen from cellulose, starch, amylose, amylopectin, galacturonan, glucuronan, chitin, chitosan, dextran, glucans, mannans, galactans, alginates, pectins, pullulan or one of their mixtures.

[0107] 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 ranging from 100 g / L to 10,000 g / L, in particular ranging from 200 g / L to 3000 g / L and typically ranging from 450 g / L to 2500 g / L.

[0108] According to the invention, "a concentration of sugar or mixtures of sugars 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.

[0109] The first starting reagent is a p-diketone which corresponds to the following formula (I):

[0110] R 1 -CO-CH2-CO-R 2 (Formula I), in which

[0111] R 1 and R 2, represent independently of one another, a linear or branched, saturated or unsaturated alkyl, hydrofluoroalkyl chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl cycle, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said cycle or said radical possibly being interrupted by one or more heteroatoms chosen from oxygen, sulfur, nitrogen.

[0112] Preferably, R 1 represents an alkyl group, such as a methyl group.

[0113] According to a preferred embodiment, the p-diketone corresponds to the compound pentane-2,4-dione (also called acetylacetone).

[0114] 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.

[0115] 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;

[0116] 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;

[0117] 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;

[0118] 4.30; 4.40; 4.50; 4.60; 4.70; 4.80; 4.90; 5.00. The first initial mixture also includes a base. For example, the base may be selected from the group consisting of: NaHCCh, Na2COa, NaOH or a combination thereof and is preferably NaOH or Na2COa.

[0119] 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.

[0120] According to the invention, "a basic quantity for an 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.

[0121] In general, said first initial mixture comprises water as LAG.

[0122] As will be detailed below, when the mechanochemistry reactor is chosen from a mill (such as a three-dimensional wet mill, a planetary mill or a vibrating mill), the first initial mixture may also include water in the form of LAG. For 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.

[0123] These different starting reagents can be introduced into the mechanochemistry reactor separately or have been previously mixed. In this case, the first initial mixture can be contained in a tank. One or more peristaltic pumps are generally used to introduce these starting reagents or the first initial mixture at an inlet of the mechanochemistry reactor.

[0124] In general, the mechanochemistry reactor has at least one grinding chamber comprising at least one inlet into which these starting reagents / first initial mixture are introduced, as well as an outlet so as to recover the desired C-glycoside (C-glycoside ketone or one of its derivatives).

[0125] 2.2) Step (B1)

[0126] Once the first initial mixture is introduced into the grinding chamber of the reactor, the first grinding stage (B1) begins.

[0127] This first initial mixture is ground at a temperature greater than or equal to 20°C, in said first mechanochemistry reactor.

[0128] According to the invention, by "temperature greater than or equal to 20°C", it is meant that the synthesis process and in particular step (B1) can be carried out at room temperature and that therefore no heating device is necessary / essential. By heating device, we mean a heating means provided within the chamber of the mechanochemistry reactor or a heating means arranged outside / around the chamber of the mechanochemistry reactor. In general, the grinding reaction (B1) is slightly exothermic and heating is observed. Thus, the temperature within the chamber of the mechanochemistry reactor during the synthesis (B1) is around 30 to 35°C (this is a temperature inherent to the reaction (B1) and not the application of a reaction temperature, the starting reagents or the first initial mixture do not need to be heated, they are introduced at room temperature (i.e.: temperature of the room where the reaction takes place, which is generally 20-25°C).

[0129] 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.

[0130] According to another embodiment, it is possible to provide a heating device within or outside the mechanochemical reactor.

[0131] According to this embodiment, the reaction temperature during the first grinding step (B1) can range from 30°C to 120°C and in particular from 40°C to 90°C. A temperature ranging from 30°C to 120°C is understood to mean all intervals between these values ​​(as described above).

[0132] The use of a heating device makes it possible to reduce the residence time of the first initial mixture during step (B1) and also to improve the yield of C-glycoside ketone.

[0133] The residence time of the first initial mixture during this first grinding stage (B1) is less than or equal to 6 hours.

[0134] According to the invention, "residence time" means the time in seconds, minutes or hours during which the first initial mixture is maintained within the grinding chamber of the mechanochemistry reactor. In general, the residence time corresponds to the reaction time allowing the synthesis of 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%.

[0135] Also according to the invention, "by 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.

[0136] In general, the residence time of the first initial mixture in the grinding chamber of the first mechanochemical reactor during step (B1) is less than 4 hours, and in particular ranges from 1 minute to 3 hours.

[0137] At the end of this first grinding step (B1), a C-glycoside ketone is obtained.

[0138] In general, depending on the reaction parameters (residence time, reaction temperature during step (B1), chosen mechanochemical reactor, etc.), the conversion of the first initial mixture into 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 measured by comparing the signals of H1 a and p of the remaining sugar and HT of the C-glycoside formed in proton NMR in D2O. Depending on the type of mechanochemical reactor chosen, the grinding step (B1) can be carried out in continuous mode in one or more passes (pendulum or recirculation mode) or in batch mode (batch). For example, the continuous mode can be obtained with a three-dimensional wet phase mill, or an extruder, while the batch mode is obtained with a planetary or vibrating mill.

[0139] Preferably, the first mechanochemical reactor is chosen from a three-dimensional wet phase mill, a planetary mill or an extruder.

[0140] 2.3) Step (C) following step (B1)

[0141] According to a first embodiment variant, the desired final C-glycoside is the ketone C-glycoside.

[0142] According to this variant, once the first grinding step has been carried out (B1), the product resulting from this step (hereinafter called final composition) and mainly comprising a C-glycoside ketone (i.e.: conversion of at least 70%) is recovered at the outlet of the first mechanochemistry reactor.

[0143] This final composition may possibly include traces of the starting reagents which have not reacted, such as for example sugar, base, etc. or even a by-product, such as a synthesis intermediate in particular if the reaction temperature, the residence time or the concentrations of the starting reagents were not within the ideal reaction ranges.

[0144] Thus, several optional steps are possible in order to extract the C-glycoside ketone.

[0145] Optionally, after this recovery step (C), the process according to the invention may comprise a step (D) of neutralization or acidification of the final composition comprising the C-glycoside ketone.

[0146] This neutralization or acidification step (D) may comprise bringing the final product (aqueous phase comprising the C-glycoside) into contact 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.

[0147] Then, the synthesis process may optionally include a concentration step (E).

[0148] Finally, the synthesis process may optionally comprise a step (F) of vacuum drying of the product obtained or freeze-drying to remove residual water, then optionally a step of purification by chromatography on silica gel and / or crystallization.

[0149] These techniques are well known to those skilled in the art and will not be described further below.

[0150] Ketone C-glycosides having the following general formula (formula (IV)) can be obtained according to the process according to the invention:

[0151] S-CH2-CO-R 2 (Formula IV) in which: S represents the sugar as defined above, i.e.: in pyranose and / or furanose form and of D and / or L series whose anomeric carbon is linked to the CH2-CO-R group;

[0152] R 2 is as defined above.

[0153] For example, the following ketone C-glycosides can be obtained according to the process of the invention:

[0154] -1-C-(pD-glucopyranosyl)-propan-2-one;

[0155] -1-C-(pD-galactopyranosyl)-propan-2-one;

[0156] -1-C-(pD-mannopyranosyl)-propan-2-one;

[0157] -1-C-(aL-fucopyranosyl)-propan-2-one;

[0158] -1-C-(aL-rhamnopyranosyl)-propan-2-one;

[0159] -1-C-(pD-xylopyranosyl)-propan-2-one;

[0160] -1-C-(p-D-ribopyranosyl)-propan-2-one;

[0161] -1-C-(p-D-arabinopyranosyl)-propan-2-one;

[0162] -1-C-(p-D-lyxopyranosyl)-propan-2-one;

[0163] -1-C-(2-désoxy-2-amino-p-D-glucopyranosyl)-propan-2-one;

[0164] -1-C-(2-désoxy-2-acétamido-p-D-glucopyranosyl)-propan-2-one;

[0165] -1-C-(2-désoxy-2-amino-p-D-galactopyranosyl)-propan-2-one;

[0166] -1-C-(2-désoxy-2-acétamido-p-D-galactopyranosyl)-propan-2-one;

[0167] -1-C-(p-D-glucopyranuronyl)-propan-2-one;

[0168] -1-C-(p-D-galactopyranuronyl)-propan-2-one;

[0169] -1-C-(p-D-idopyranuronyl)-propan-2-one;

[0170] -1-C-p-(a-D-glucopyranosyl-(1^4)-D-glucopyranosyl)-propan-2-one;

[0171] -1-C-p-(p-D-glucopyranosyl-(1^4)-D-glucopyranosyl)-propan-2-one;

[0172] -1-C-p-(p-D-galactopyranosyl-(1^4)-D-glucopyranosyl)-propan-2-one;

[0173] -1-C-p-(a-D-glucopyranosyl-(1^4)-a-D-glucopyranosyl-(1^4)-D-glucopyranosyl)- propan-2-one;

[0174] -1-C-p-(p-D-xylopyranosyl-(1^4)-D-xylopyranosyl)-propan-2-one;

[0175] -1-C-p-(p-D-xylopyranosyl-(1— >4)-p-D-xylopyranosyl-(1— >4)-D-xylopyranosyl)-propan-2- one;

[0176] -1-C-p-(p-D-xylopyranosyl-(1— >4)-p-D-xylopyranosyl-(1— >4)-D-xylopyranosyl)-propan-2- one;

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

[0178] -1 -C-p-(p-D-xylopyranosyl-(1 -^4)-p-D-xylopyranosyl-(1 -^4)-p-D-xylopyranosyl -(1 -^4) -p- D-xylopyranosyl-4-D-xylopyranosyl)-propan-2-one;

[0179] -1-C-p-(p-D-xylopyranosyl-(1— >4)-p-D-xylopyranosyl-(1— >4)-p-D-xylopyranosyl-(1— >4) -p- D-xylopyranosyl -(1^4)-p-D-xylopyranosyl-4-D-xylopyranosyl)-propan-2-one. 2.4) Etape (B2)

[0180] According to another embodiment variant, the desired final C-glycoside is not the ketone C-glycoside obtained at the end of step (B1), but another C-glycoside of interest, such as a C-glycoside-enone (i.e.: other chemical functionalization).

[0181] According to this variant, once the first grinding step has been carried out (B1), a second grinding step (B2) is carried out.

[0182] According to the invention, this second grinding step (B2) is carried out after step (B1) either in the first mechanochemical reactor or in a second mechanochemical reactor, different from the first.

[0183] Indeed, according to one embodiment, steps (B1) and (B2) of the synthesis process according to the invention are carried out in the same mechanochemistry reactor. According to this embodiment, it is thus 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) (i.e., between step (B1) and step (C)).

[0184] 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)).

[0185] 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.

[0186] 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. steps. Indeed, the conversion into C-glycoside ketone at the end of step (B1) is very good and thus, step (B2) can be carried out directly and in the same mechanochemistry reactor.

[0187] The starting reagents for carrying out this second grinding (B2) and forming hereinafter the second initial mixture are as follows: the C-glycoside ketone previously formed at the end of step (B1), called starting C-glycoside ketone and a second starting reagent.

[0188] 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.

[0189] Preferably, the functionalization reaction is chosen from:

[0190] - an aldolization-crotonization reaction so as to obtain a C-glycoside having an unsaturated a,p ketone function, such as a C-glycoside-enone

[0191] - an addition reaction of O-, A / -, S-, C-nucleophiles, preferably aliphatic or aromatic / V-nucleophile, in order to obtain a C-glycoside imine. The choice of the second starting reagent will depend on the desired C-glycoside of interest and thus on the desired functionalization on the aglycone linked to the sugar.

[0192] In particular, said second starting reagent is chosen from a compound of formula (H) and / or (III) n

[0193] (Formula II)

[0194] R 3in which R 3 is selected from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R 3 is a hydrogen atom and R 4 is selected from the group consisting of: -CHO, CH2NH2; and / or

[0195] R 5 -CHO (Formula III) in which R 5 is chosen from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms.

[0196] In particular, the second starting reagent is chosen from: benzaldehyde or benzylamine.

[0197] For example, if the second starting reactant is benzaldehyde, a C-glycoside-enone is formed.

[0198] By C-enone glycoside is meant a C-glycoside in which the C-anomeric bond is connected to an aglycone comprising an enone function.

[0199] According to this embodiment, the chemical reaction to form a C-enone glycoside can be schematized as follows (the first starting reagent is pentane-2,4-dione and the second starting reagent is benzaldehyde):

[0200] (Bl) (B2)

[0201] In particular, the amount of the second starting reagent per 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.

[0202] The second initial mixture may also include the addition of a complementary base (in addition to that already present at the end of step (B1)). The presence or absence of the complementary base will depend on the type of mechanochemistry reactor used and the choice of the second starting reagent. For example, when the second mechanochemistry reactor is chosen from a three-dimensional wet mill, it is preferable to introduce a complementary base, whereas this is not always necessary with the planetary mill.

[0203] For example, the complementary base is selected from the group consisting of: NaHCOs, Na2CC>3, NaOH or a combination thereof. When present, the amount of complementary base per one equivalent (eq.) of C-glycoside ketone ranges from 0.3 to 3 eq., preferably from 0.5 to 2 eq and typically ranges from 0.5 to 1 eq.

[0204] According to the invention, an equivalent quantity ranging 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.

[0205] Finally, the second initial mixture may include water as LAG (and not as a solvent), in particular when the second mechanochemical reactor is chosen from a grinder (three-dimensional grinder, planetary grinder or even vibrating grinder). 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 it in order to carry out this step (B2).

[0206] The pH is thus greater than 7 and generally varies from 8 to 12.

[0207] As for step (A) mentioned above, the starting reagents (the second starting reagent and where appropriate 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 mixed beforehand.

[0208] The residence time during this step (B2) of the second initial mixture 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.

[0209] Also according to the invention, "by 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.

[0210] This residence time will be adapted by the person skilled in the art depending on the desired functionalization.

[0211] 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 mechanochemistry 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.: other chemical functionalization) with preferably a conversion of at least 75%, in particular at least 80% and typically at least 90%, or even better 99% (the conversion is measured by proton NMR analysis of the crude in D2O).

[0212] As for step (B1), the second initial mixture is ground at room temperature, namely at a temperature greater than or equal to 20°C, in said second mechanochemical reactor. The definitions (room temperature, temperature greater than or equal to 20°C, heating device, etc.) are the same as those indicated above and are not reproduced below.

[0213] According to an alternative embodiment, no internal or external heating device is provided to carry out the grinding step (B2). Generally, the reaction (B2) is also slightly exothermic and heating is observed. Thus, the temperature within the chamber of the second mechanochemistry reactor during the synthesis (B2) is around 30 to 35°C (this is a temperature inherent to the reaction (B2) and not the application of a reaction temperature via a heating device (the starting reagents or the second initial mixture do not need to be heated, they are introduced at room temperature (i.e.: temperature of the room where the reaction takes place which is generally 20-25°C)).

[0214] According to another embodiment, it is possible to provide a heating device within or outside the mechanochemistry 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 all intervals between these values ​​(as described above).

[0215] 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.

[0216] Depending on the type of mechanochemical reactor chosen, the grinding step (B2) can be carried out in continuous mode in one or more passes (pendulum or recirculation mode) or in discontinuous mode (batch). For example, the continuous mode can be obtained with a three-dimensional wet mill, or an extruder, while the discontinuous mode is obtained with a vibrating mill or a planetary mill.

[0217] Preferably, the second mechanochemical reactor is chosen from a three-dimensional wet phase mill, a planetary mill or an extruder.

[0218] In general, depending on the reaction parameters (residence time, reaction temperature during step (B2), chosen mechanochemical reactor, etc.), the conversion of the second initial mixture into 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 measured by proton NMR analysis of the crude in D2O. 2.5) Step (C) following step (B2)

[0219] Once the second grinding step (B2) has been carried out, step (C) of recovering the final composition comprising the C-glycoside of interest, such as a C-enone glycoside or a C-imine glycoside, is carried out.

[0220] 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 those skilled in the art.

[0221] For example, for the reaction to obtain a C-glycoside-enone, the final composition from step (B2) can be passed through an Amberlite® resin so as to obtain a neutral pH (of the order of 7).

[0222] For example, the following C-enone glycosides can be obtained according to the process of the invention:

[0223] (E)-4-phenyl-1-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2 / 7-pyran-2-yl)but-3-en-2-one

[0224] (E)-4-phenyl-1-(3,4,5-trihydroxy-tetrahydro-2 / 7-pyran-2-yl)but-3-en-2-one

[0225] (E)-4-(4-methoxyphenyl)-1-(3,4,5-trihydroxy-tetrahydro-2 / 7-pyran-2-yl)but-3-en-2-one

[0226] (E)-4-(4-dimethylaminophenyl)-1-(3,4,5-trihydroxy-tetrahydro-2 / 7-pyran-2-yl)but-3-en-2-one.

[0227] For example, the following C-glycosides-imine can be obtained according to the process of the invention:

[0228] - (2S,3R,4S,5R)-2-((E)-2-(benzylimino)propyl)tetrahydro-2H-pyran-3,4,5-triol

[0229] - (2S,3R,4S,5R)-2-((E)-2-(tetradecylimino)propyl)tetrahydro-2H-pyran-3,4,5-triol.

[0230] 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).

[0231] 3) Mechanochemical reactors suitable for carrying out the process according to the invention

[0232] According to the invention, the mechanochemical reactor(s) which can be used to carry out the process according to the invention are the following:

[0233] - of the type of mill operating in continuous mode such as a planetary ball mill or a three-dimensional wet phase mill or;

[0234] - of the crusher type operating in batch mode like a planetary ball mill, or a vibrating mill,

[0235] - extruder type such as a co-rotating twin-screw extruder.

[0236] These different reactors will be described below. 3.1) Planetary ball mill

[0237] As is known, a planetary ball mill comprises one or more grinding bowls arranged on a sun wheel. The bowl(s) each comprise grinding balls. The grinding bowls are arranged eccentrically on the sun wheel of the planetary ball mill.

[0238] The sun wheel rotates in the opposite direction to the grinding bowls in a ratio of 1:2 or 1:2.5 or 1:3. Under the effect of the centrifugal forces generated by the rotation, the balls start moving and hit the inner wall of the bowl after passing through the material to be ground. Grinding is mainly carried out by impact and friction.

[0239] For example, the PULVERISETTE 7 premium line (P7PL) planetary mill from Fritsch is suitable for carrying out the process according to the invention.

[0240] In particular, this type of planetary mill has two stainless steel bowls that allow two reactions to be carried out in parallel. The bowl can have a capacity of 20 mL and include 60 to 100 balls, preferably 80 balls of 5 mm diameter or 10 balls of

[0241] 10 mm diameter. A counterweight is placed in the grinder when using a single bowl.

[0242] There are also larger planetary mills with 45 mL bowls that are loaded with 180 5 mm diameter balls or 18 10 mm diameter balls.

[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] In order to carry out the process according to the invention, and in particular the grinding step (B1), the first initial mixture comprises at least the first starting reagent p-diketone, the base and a small amount of water (LAG). This first initial mixture is introduced into the bowl of the planetary ball mill. For this step (B1) in the planetary ball mill, it is generally required to add a small amount of liquid in order to improve the reactivity of the synthesis. The LAG may represent, for example, 0.4 mL for a 20 mL grinding bowl loaded with 80 5 mm balls.

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

[0246] - the concentration of sugar or mixture of sugars (monosaccharide, oligosaccharide and / or polysaccharide) in the first initial mixture is greater than or equal to 250 g / L, preferably ranges from 1000 g / L to 10000 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 one 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.; - The LAG has a q value preferably ranging from 0 to 2, preferably less than or equal to 1 and typically less than or equal to 0.2;

[0249] - reaction (B1) is carried out without the use of an external heating device (the planetary ball mill generally does not have a heating device);

[0250] - the first initial mixture is thus introduced and ground during step (B1) at room temperature, of the order of 20°C-25°C (heating is however observed during the reaction (B1) and the temperature within the mill can rise to 30-35°C);

[0251] - the residence time of the first initial mixture during this first grinding step (B1) is less than or equal to 6 hours, preferably ranging from 90 minutes to 4 hours and typically ranging from 2 hours to 3.5 hours;

[0252] - the cycles are 4 to 50 in number, in particular 10 to 45 and typically 20 to 40, each cycle having a duration of the order of 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 carried out between each cycle;

[0253] - the rotation speed of the bowls preferably varies from 800 rpm to 200 rpm, in particular from 600 rpm to 300 rpm and typically from 500 rpm to 300 rpm, such as 400 rpm;

[0254] - the conversion of the initial mixture into C-glycoside ketone ranges from 70 to 100%.

[0255] 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 (B1) is already present, so as to form the second starting mixture.

[0256] The reaction parameters are advantageously the following when the second mechanochemical reactor is chosen from a planetary ball mill:

[0257] - the quantity of said second starting reagent, for one equivalent (eq.) of said at least one starting C-glycoside ketone, varies from 0.75 to 3 eq., preferably varies from 1 to 2.5 eq and typically varies from 1 to 1.5 eq.;

[0258] - adding a complementary base is not necessarily useful for carrying out this step (B2);

[0259] - similarly, it is not necessary to add water in the form of LAG to carry out this step (B2);

[0260] - reaction (B2) is carried out without the use of an external heating device (the planetary ball mill generally does not have a heating device);

[0261] - the second initial mixture is thus introduced and ground during step (B2) at room temperature, of the order of 20°C-25°C (heating is however observed during the reaction (B2) and the temperature within the mill can rise to 30-35°C);

[0262] - the residence time of the second initial mixture during this second grinding step (B2) is less than or equal to 6 hours, preferably ranging from 20 minutes to 3 hours and typically ranging from 30 minutes to 1.5 hours, such as 1 hour; - the rotation speed of the bowls preferably varies from 800 rpm to 200 rpm, in particular from 600 rpm to 300 rpm and typically from 500 rpm to 300 rpm, such as 400 rpm;

[0263] - the conversion of the second initial mixture into a C-glycoside ketone derivative ranges from 70 to 100%.

[0264] 3.2) Three-dimensional wet mill, i.e. in the presence of water as LAG

[0265] Such a crusher will be described with reference to Fig.2.

[0266] As illustrated in this figure, the three-dimensional crusher 1 comprises at least:

[0267] - a stationary grinding chamber 2 of generally cylindrical shape extending along a longitudinal axis XX, said stationary chamber 2 being preferably filled at least in part with grinding balls (not shown) and comprising: at a first end 3 at least one inlet 5 serving to introduce the first initial mixture or the second initial mixture, and at a second end 4, an outlet 6 comprising a separation means 7 capable of discharging only the final mixture thus formed in said chamber 2; and

[0268] - an agitator 8, arranged in the stationary grinding chamber, in the form of an elongated rod along the longitudinal axis XX, said agitator 8 being capable of setting the microbeads / starting suspension assembly in motion.

[0269] In particular, the inlet 5 is generally connected to at least one peristaltic pump (not shown). This pump makes it possible to bring the starting reagents / first initial mixture or second initial mixture, contained for example in one or more containers, such as one or more tanks, into the grinding chamber 2 via the inlet 5. The pump also makes it possible, during operation of the three-dimensional grinder, to bring the starting reagents / first initial mixture or second initial mixture at a certain flow rate which is adjustable, hereinafter called the “passage flow rate”. This passage flow rate also forms a current in the grinding chamber 2 making it possible to drive the starting suspension from the inlet 5 to the outlet 6.

[0270] The outlet 6 of the grinding chamber 2 comprises in particular the separation system 7 which makes it possible to separate any balls from the final composition obtained at the end of step (B1) or (B2) comprising mainly the C-glycoside (C-glycoside ketone or C-glycoside ketone derivative), the LAG and possibly the raw material(s) which have not reacted.

[0271] The internal wall 9 of the grinding chamber 2 comprises, according to a first embodiment, a smooth internal surface. However, according to an alternative embodiment which will be described below, fingers 11 may be arranged on this internal surface 9.

[0272] 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. In particular, the agitator 8 is able to rotate around the X axis via a rotary shaft (14, Fig. 3) to impart within the grinding chamber 2 a swirling movement 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.

[0273] In general, the mill suitable for carrying out the method according to the invention comprises a grinding chamber having a diameter of 75 mm to 300 mm for 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 grinding chamber varies from 0.35 L to 600 L, preferably from 0.35 L to 62 L.

[0274] The geometry of the grinding chamber and the agitator may be adjusted by a person skilled in the art depending on the desired conversion, as well as the desired reaction time. For example, it is also possible for the grinding chamber 2 to include an accelerator in order to improve the grinding of the starting suspension.

[0275] According to a first embodiment, the grinding chamber 2 does not include grinding balls.

[0276] According to a second embodiment, the grinding chamber 2 comprises grinding balls.

[0277] When present, the balls housed in the grinding chamber 2 and suitable for the method 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 of the order of 0.5 to 1 mm. Preferably, the diameter of the microbeads is less than or equal to 1 mm.

[0278] They are preferably chosen from balls with high hardness and relatively good resistance to abrasion.

[0279] In particular, the balls have a Vickers hardness measured according to standard EN ISO 6507-1 greater than or equal to 900 HV1, preferably ranging from 900 HV1 to 1600 HV1, typically ranging from 1000 to 1400 HV1.

[0280] Advantageously, they have a high actual density. In general, the microbeads according to the invention have an actual density greater than or equal to 2 g / cm 3, in particular ranging from 2 to 15 g / cm 3 , preferably 3 to 12 g / cm 3 , and typically 4 to 10 g / cm 3 .

[0281] Thus, the balls according to the invention may be ceramic balls (zirconium oxide ZrO2, zirconium silicate ZrSiCl); steel microbeads, tungsten carbide microbeads, glass microbeads or a combination thereof. Preferably, the balls are ceramic because they do not generate pollution through their wear. In particular, the balls are made of zirconium oxide.

[0282] In particular, the balls represent, by volume, relative to the total volume of the stationary chamber 2, from 50% to 85%, preferably from 55% to 70%. For example, the three-dimensional wet-phase microbead mill suitable for carrying out the method 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 LS1, or Alpine Hosokawa, for example, Agitated Media Mill AHM.

[0283] For example, a three-dimensional mill marketed by the company WAB (Willy A. Bachofen SARL) of the AP05 type has an agitator with 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 the AP2 type, 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.

[0284] According to a characteristic of the invention, the three-dimensional wet phase grinder may comprise an internal heating device, as described in particular in patent application WO 2019 / 228983.

[0285] The reaction parameters are advantageously the following when the first mechanochemistry reactor is chosen from a three-dimensional microbead mill:

[0286] - the concentration of sugar or mixture of sugars (monosaccharide, oligosaccharide and / or polysaccharide) in the first initial mixture is greater than or equal to 100 g / L, preferably ranging from 100 g / L to 2000 g / L, in particular ranging from 200 g / L to 1500 g / L and typically ranging from 450 g / L to 900 g / L;

[0287] - 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.;

[0288] - 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.;

[0289] - The LAG has a q value preferably ranging from 0 to 2, preferably < 1 and typically < 0.2;

[0290] - the reaction (B1) can be carried out with or without the use of an external heating device, preferably the mill does not include a heating device;

[0291] - according to this embodiment, the first initial mixture is thus introduced and stirred during step (B1) at room temperature, of the order of 20°C-25°C (heating is however observed during the reaction (B1) and the temperature within the mill can rise to 30-35°C)

[0292] - reaction (B1) can be carried out with the use of an external heating device (the mill comprises a heating device such as an induction heating device);

[0293] - according to this embodiment, the first initial mixture is thus introduced and stirred during step (B1) while 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 (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);

[0294] - this embodiment has the advantage of providing a precise reaction temperature, regardless of the flow rate or temperature of the starting reagents / first or second initial mixture Tl at the inlet of the mill (better heating of the flow forming the initial mixture); this embodiment is also particularly suitable for an embodiment where several successive grindings are carried out in one-pot;

[0295] - the residence time of the first initial mixture during this first grinding step (B1) is less than or equal to 6 hours, preferably ranging from 50 minutes to 4 hours and typically ranging from 1 hour to 3.0 hours;

[0296] - the reaction (B1) takes place continuously, namely during the determined residence time, the product is continuously recovered at outlet 6 of the grinder (via for example a pump) and reintroduced into inlet 5;

[0297] - 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;

[0298] - the residence time is inherent to the apparent volume of any balls and the flow rate;

[0299] - for example, if the total apparent volume of the balls is 270 cm 3 (balls with an apparent density of 3.7 g / cm 3 ) and that the introduction flow rate of the first or second initial mixture is 45 L / h, or 12.45 cm 3 / 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 density of the microbeads, as well as the flow rate;

[0300] - “apparent volume” means the volume of the beads including the interstitial air between the beads - the apparent density is the ratio between the mass of the microbeads and the apparent volume;

[0301] - 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 the microbeads is suitable, for example, for a three-dimensional mill comprising a stationary chamber 1 of 500 mL;

[0302] - the agitator 10 via its elongated rod 11 can have a rotation speed 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;

[0303] - 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);

[0304] - the conversion of the first initial mixture into C-glycoside ketone ranges from 80 to 100%.

[0305] 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 (B1) is already present, so as to form the second initial mixture. The reaction parameters are advantageously as follows when the second mechanochemistry reactor is chosen from a three-dimensional wet-phase mill:

[0306] - the quantity of said second starting reagent, for one equivalent (eq.) of said at least one starting C-glycoside ketone, varies from 0.75 to 3 eq., preferably varies from 1 to 2.5 eq and typically varies from 1 to 1.5 eq.;

[0307] - the base may be chosen from Na2COs or NaOH in an amount per equivalent (eq.) of said at least one C-glycoside ketone ranging from 1.2 to 1.5 eq.;

[0308] - it is not necessary to add water / LAG to carry out this step (B2) (the water / LAG is already present in the grinder in the wet phase);

[0309] - according to an alternative embodiment, the reaction (B2) is carried out without the use of an external heating device;

[0310] - according to this method, the second initial mixture is thus introduced and stirred during step (B2) at room temperature, of the order of 20°C-25°C (heating is however observed during the reaction (B2) and the temperature within the mill can rise to 30-35°C);

[0311] - according to another embodiment, the reaction (B2) can be carried out with the use of a heating device (the mill comprises a heating device such as an induction heating device);

[0312] - according to this embodiment, the second initial mixture is thus introduced and stirred during step (B2) while 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.

[0313] - the residence time of the first initial mixture during this first grinding step (B1) is less than or equal to 6 hours, preferably ranging from 1 minute to 4 hours and typically ranging from 1 minute to 3.0 hours;

[0314] - the reaction (B2) takes place continuously, namely during the determined residence time, the product is continuously recovered at outlet 6 of the grinder (via for example a pump) and reintroduced into inlet 5;

[0315] - the flow rate during the reaction (B2) 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;

[0316] - the residence time is inherent to the apparent volume of any balls and the flow rate;

[0317] - 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;

[0318] - the agitator 10 via its elongated rod 11 can have a rotation speed 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; - 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;

[0319] - the conversion of the second initial mixture into C-glycoside ketone derivative ranges from 80 to 100%.

[0320] 3.3) Vibrating crusher

[0321] A vibrating mill can be a vibrating mill (longitudinal movement with a frequency of up to 30 Hz, for example) or a vibrational mill (three-dimensional figure-of-eight movement with a frequency of up to 18 Hz).

[0322] A vibrating mill suitable for the invention may, for example, correspond to that marketed by the company Retsch or Spex.

[0323] In general, the parameters of the synthesis process according to the invention are similar to those mentioned above for the planetary microbead mill.

[0324] 3.4) Extruder

[0325] 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, or interpenetrating screws). As is known, a twin-screw extruder comprises two screws, generally parallel, rotating inside a barrel whose section has the shape of an eight.

[0326] For 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. This type of extruder also includes an inlet connected to a pump in order to introduce the starting reagents in solid form.

[0327] Fig. 3 illustrates a type of extruder allowing the process for synthesizing C-glycosides according to the invention to be carried out continuously.

[0328] This figure illustrates an interpenetrating coratative twin-screw extruder 100. In a known manner, the extruder 100 comprises two endless screws 103 which rotate inside a cylindrical barrel 106 thanks to a motorization group 105, the barrel 106 is temperature-regulated 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 motorization group 106, while the second starting reactant(s) can be introduced via a second hopper 102 connecting the barrel in its middle. The final product resulting from this or these reactions exits at the level of the die 104.The feed nozzle 101 is thus able to introduce the first starting reagents in powder (solid) form / first initial mixture, also the feed nozzle 102 is able to introduce the first starting reagents / first initial mixture also in solid form.

[0329] In order to introduce the starting reagents in liquid form, it is possible for the extruder to include an inlet, arranged near the nozzle 101 and / or the nozzle 102 which is provided for this purpose. This inlet is connected to a pump and thus makes it possible to introduce the liquid reagent(s) at a certain flow rate.

[0330] In order to carry out the grinding step (B1) of the method according to the invention, a first mixture in powder form comprising the sugar and the base is prepared and introduced via the feed nozzle 101. The extrusion method does not require the use of water as LAG. The first starting reactant (liquid) is introduced via a pump into the inlet provided for this purpose. The first grinding takes place in the barrel.

[0331] The reaction parameters are the same as those presented above in paragraph 2°) synthesis process.

[0332] 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.

[0333] 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 to carry out the grinding by introducing the C-glycoside ketone via the nozzle 101 and the second starting reagent via the inlet provided for this purpose.

[0334] 4) Use

[0335] The invention also relates to the use of a first and / or a second mechanochemical reactor, for synthesizing a C-glycoside, such as a C-glycoside ketone, a C-glycoside ketone derivative, such as a C-glycoside enone, or a C-glycoside imine.

[0336] 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.

[0337] EXAMPLES

[0338] The description of the tests below is given as a purely illustrative and non-limiting example.

[0339] Example 1: Synthesis in a planetary ball mill

[0340] A) General procedure

[0341] A1 - Raw materials

[0342] For testing, the starting raw materials are as follows:

[0343] [Table 1] k2 - Planetary mill for mechanical synthesis

[0344] For this example 1, a planetary mill for mechanical synthesis 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 of 5 mm diameter, allow two reactions to be carried out in parallel. A counterweight is placed in the mill when using a single bowl. The grindings are carried out during five-minute cycles with a one-minute pause between each cycle, with a rotation speed of 500 rpm in reverse mode. The plate and the reactors do not rotate in the same direction; the rotation allows the balls to impact the walls of the bowls.

[0345] A small amount of liquid (hereinafter referred to as LAG), of the order of 0.4 mL of water, is added to improve reactivity (not considered a solvent).

[0346] A3 - Synthesis process using the PULVERISETTE 7 mill

[0347] Synthesis of C-glycoside ketone

[0348] The monosaccharide (1 eq.) and the base (1.2 or 1.5 eq.) are placed in a 20 mL stainless steel bowl loaded with 80 stainless steel balls of 5 mm diameter. Pentane-2,4-dione is added, as well as LAG (H2O; Eta (LAG factor=0.2). The reaction time in the P7PL planetary mill varies depending on the monosaccharide (see Table 2). The product in the form of a paste is recovered by solubilization in H2O inside the bowl, the solution is neutralized (pH=5) with an Amberlite resin (IR-120 H+) and then evaporated. The crude reaction product is analyzed by NMR.

[0349] The reaction is carried out without external heating.

[0350] Synthesis of C-enone glycoside

[0351] 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 stated above. The second reaction consists of adding benzaldehyde to the reactor once the first reaction is finalized and possibly base. The residence time is 12 cycles of 5 minutes with a rest time of 1 minute between each cycle (i.e. 71 minutes).

[0352] Similarly, the reaction is carried out without external heating. The final product is then neutralized. B) Experimental conditions and results

[0353] B1 - Synthesis of C-glycoside ketone [Table 2]: Experimental conditions

[0354] [Table 3]: Results

[0355] Thus, a process in a planetary mill allows the synthesis of C-glycoside ketone. For example, a conversion of 100% is obtained from the monosaccharide D-xylose after 143 minutes (24 cycles / grinding of 5 minutes including 1 min break between each cycle) or a conversion of more than 95% is obtained from an oligosaccharide (D-maltose) or a monosaccharide D-xylose using a different first starting reagent (namely hepta-3,5-dione or 1,3-diphenylprop-1,3-dione) after 143 minutes (24 cycles / grinding of 5 minutes including 1 min break between each cycle). B2 - Synthesis of C-glycoside-enone according to the process of the invention using the planetary mill

[0356] [Table 4]: Experimental conditions (1 ère stage)

[0357] [Table 5]: Experimental conditions (2 ème stage)

[0358] [Table 6]: Results

[0359] The process according to the invention in a planetary mill makes it possible to form C-glycoside-enone continuously (12 cycles / grindings of 5 minutes). In particular, it makes it possible to form C-glycoside-enone without removing the C-glycoside ketone formed at the end of step 1 from the mill (i.e.: without an intermediate neutralization step).

[0360] Example 2: Synthesis in a three-dimensional mill in LAG mode

[0361] A) General procedure

[0362] A1 - Raw materials

[0363] For testing, the starting raw materials are as follows: [Table 7]

[0364] A2 - Three-dimensional wet microbead mill

[0365] For this example 2, a Dynomill ECM AP-05 three-dimensional microbead mill from Willy A. Bachofen AG (WAB) was used. This mill contains 1.235 kg of microbeads and has been adapted to include a heating device. Thus, the mill comprises a heating device positioned at the inlet of the stationary chamber, and the first mixing member acts as a susceptor (document WO 2019 / 228983).

[0366] In particular, the heating device has the following characteristics: [Table 8]

[0367] The microbeads are made of zirconium oxide and have a diameter of 0.5 mm and are marketed under the brand name Zirmil® Y Ceramic Beads by Saint-Gobain. 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.

[0368] In operation, the microbeads are stirred by a stirrer at a rotation speed that can vary from 0.01 to 16 m / s. The stirrer also has chrome-plated cast iron mixing discs.

[0369] A3 - Synthesis process of C-glycoside ketone using three-dimensional wet mill

[0370] A first initial mixture comprising the monosaccharide, the base, the first reagent and water are first mixed vigorously by magnetic stirring at 25°C in a tank (the experimental conditions are illustrated in the table below).

[0371] The first mixture is pumped using a peristaltic pump at a flow rate of 200 mL / min and the flow 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 allows the grinding chamber to be heated to a temperature of 90°C. The mill operates continuously (the product leaving through outlet 6 is reintroduced into inlet 5 of the grinding chamber).

[0372] The final product is then neutralized.

[0373] After a certain residence time in the mill, the reaction medium is analyzed by NMR spectroscopy and by mass spectrometry.

[0374] B) Experimental conditions and results

[0375] Table 9]: Experimental conditions

[0376] [Table 10]: Results

[0377] Thus, the synthesis process according to the invention using a three-dimensional microbead mill makes it possible to continuously produce a C-glycoside ketone with a conversion ranging from 88 to 100%.

[0378] Example 3: Synthesis in a three-dimensional mill (Dyno®-Mill Research lab from Willy A. Bachofen AG or WAB IMPA°CT REACTOR® from Willy A. Bachofen AG) in LAG mode with or without beads and from various sugars

[0379] A) General procedure

[0380] A1 - Raw materials

[0381] For testing, the starting raw materials are as follows:

[0382] [Table 11]

[0383] A2 - Three-dimensional mill with wet-phase microbeads

[0384] For this example 3, a Dyno®-mill Research Lab three-dimensional microbead mill from Willy A. Bachofen AG (WAB) was used (no heating system; the process is carried out at ambient temperatures). Depending on the tests, this mill contains no beads or 0.18 and 0.10 kg of microbeads. The microbeads are made of zirconium oxide and have a diameter of 0.5 mm and are marketed under the brand name Zirmil® Y Ceramic Beads by Saint-Gobain.

[0385] The grinding chamber of the mill has a capacity of 80 mL and is filled, in volume, relative to its total volume and depending on the tests, between 0 and 0.50 mL of the microbeads described above.

[0386] In operation, the microbeads are stirred by a stirrer at a rotation speed that can vary from 0.01 to 16 m / s. The stirrer also has mixing discs made of chrome cast iron.

[0387] A3- Three-dimensional grinder without microbeads in wet phase

[0388] This experiment was carried out in a mill marketed by WAB under the trade name WAB IMPA°CT REACTOR® without microbeads (reactor volume 500mL). The reaction is carried out in recirculation mode. The product that comes out through outlet 6 is reintroduced into inlet 5 of the grinding chamber (Fig.2):

[0389] - the recirculation flow rate is 750ml / min;

[0390] - the stirring speed is 10 m / s.

[0391] A4 - Synthesis process of C-glycoside ketone using three-dimensional wet mill

[0392] A first initial mixture comprising the monosaccharide, the base, the first reagent and water are first mixed vigorously by magnetic stirring at 25°C in a tank (the experimental conditions are illustrated in the table below).

[0393] The first mixture is pumped using a peristaltic pump at a flow rate of 50 mL / min and the flow is introduced into the three-dimensional mill described above. The agitator rotates at 10 m / s. The mill operates continuously (the product leaving outlet 6 is reintroduced into inlet 5 of the grinding chamber).

[0394] The final product is then neutralized.

[0395] After a certain residence time in the mill, the reaction medium is analyzed by NMR spectroscopy and by mass spectrometry.

[0396] B) Experimental conditions and results

[0397] [Table 12]: Experimental conditions (without microbeads)

[0398] [Table 13]: Results

[0399] Thus, the synthesis process according to the invention using a three-dimensional mill without microbeads makes it possible to continuously produce a C-glycoside ketone with a conversion greater than or equal to 97%.

[0400] [Table 14]: Experimental conditions (with microbeads)

[0401] [Table 15]: Results Thus, the synthesis process according to the invention using a three-dimensional mill with microbeads makes it possible to continuously produce a pC-galactoside with a conversion greater than or equal to 97%.

[0402] [Table 16]: Experimental conditions (with microbeads)

[0403] [Table 17]: Results

[0404] [Table 18]: Experimental conditions (with microbeads)

[0405] [Table 19]: Results

[0406] Thus, the synthesis process according to the invention using a three-dimensional mill with microbeads makes it possible to continuously produce a pC-mannoside with a conversion greater than or equal to 97%.

[0407] [Table 20]: Experimental conditions (with microbeads)

[0408] [Table 21]: Results Thus, the synthesis process according to the invention using a three-dimensional mill with microbeads makes it possible to continuously produce a pC-glucoside with a conversion greater than or equal to 97%.

[0409] Example 4: Synthesis of C-glycoside-ketone in an extruder (Fig.4 and 5)

[0410] For this example, a pharma 11 twin-screw extruder (Thermo Fisher Scientific) was used.

[0411] D-glucose (50 g, 1 eq) is ground with NaOH base (12.11 g, 1 eq) in a mortar. The powder mixture is added to 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 heating or external heating input).

[0412] The rotation speed of the twin screw is 80 rpm.

[0413] The stay time is 20 minutes.

[0414] Samples were taken at the screw outlet and analyses by TLC, MS and NMR show the presence of the expected C-glucoside as well as that of unreacted glucose. The reference example corresponds to example 3 (Table 2) described above.

[0415] As examples 1 to 3 above illustrate, the method according to the invention thus makes it possible to:

[0416] - synthesize C-glycosides with or without solvent, over shorter times and / or lower temperatures than the literature, and in a continuous manner.

[0417] - carry out multiple “one pot sequential” syntheses allowing the functionalization of C-glycosides, in the same reactor, without intermediate purification steps

Claims

Claims 1. 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 pyranose and / or furanose form and of D and / or L series, said sugar having at least one hydroxyl function in the anomeric position which is necessarily free, of a first starting reagent which is a p-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 C-glycoside ketone; (C) the recovery at the outlet of the first mechanochemistry reactor of a final product comprising said at least C-glycoside.

2. The synthesis method of 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 first initial 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, in which 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. Synthesis method according to any one of the preceding claims, in which said at least one sugar is chosen from: a monosaccharide, an oligosaccharide having from 2 to 10 sugar units or a polysaccharide having more than 11 sugar units and one of their mixtures.

6. Synthesis method according to claim 5, wherein said monosaccharide is chosen 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, / V-acetyl-D-glucosamine, / V-acetyl-D-galactosamine and advantageously denotes D-glucose, D-xylose, / V-acetyl-D-glucosamine or L-fructose, and very preferably D-xylose; or said oligosaccharide is chosen 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 chosen from D or L-iduronic acid or D-glucuronic acid with a hexosamine chosen from D-galactosamine, D-glucosamine, / V-acetyl-D-galactosamine, / V-acetyl-D-glucosamine, an oligosaccharide containing at least one xylose advantageously chosen from xylobiose, methyl-p-xylobioside, xylotriose, xylotetraose, xylopentaose and xylohexaose and preferentially xylobiose which is composed of two xylose molecules linked by a beta-1-4 bond, or said polysaccharide is chosen 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. Synthesis process according to any one of the preceding claims, in which said first starting reagent which is a p-diketone corresponds to the following formula (I): R 1 -CO-CH2-CO-R 2 (Formula I), in which R 1 and R 2 , represent independently of one another, a linear or branched, saturated or unsaturated alkyl, hydrofluoroalkyl chain, a cycloalkyl, cycloperfluoroalkyl, cyclohydrofluoroalkyl cycle, comprising from 1 to 18 carbon atoms, a phenyl or benzyl radical, said chain, said cycle or said radical possibly being interrupted by one or more heteroatoms chosen from oxygen, sulfur, nitrogen, preferably R 1 represents an alkyl group, such as a methyl group.

8. Synthesis process according to any one of the preceding claims, wherein 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 to 10,000 g / L, in particular ranges from 200 g / L to 3000 g / L and typically ranges from 450 g / L to 2800 g / L.

9. Synthesis process according to any one of the preceding claims, wherein during 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. Synthesis method according to any one of the preceding claims, wherein during step (A), the amount of base 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. Synthesis method according to any one of the preceding claims, comprising at least: (B2) a second grinding carried out in said first mechanochemistry reactor after step (B1) or carried out in a second mechanochemistry reactor, different from the first mechanochemistry reactor after step (C), from a second initial mixture comprising at least said C-glycoside ketone previously formed at the end of step (B1), called 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 method according to claim 11, wherein said second grinding (B2) is carried out directly after step (B1) and in said first mechanochemistry reactor.

13. Synthesis method according to claim 11 or 12, in which said functionalization reaction is chosen from: - an aldolization-crotonization reaction, so as to obtain a C-glycoside having an unsaturated a,p ketone function, like a C-glycoside-enone, - an addition reaction of O-, A / -, S-, C-nucleophiles, preferably aliphatic or aromatic / V-nucleophile, in order to obtain a C-glycoside imine.

14. Method according to any one of claims 11 to 13, in which during step (B2), said second starting reagent is chosen from: - a compound of formula (II) (Formula II) in which R 3 is selected from the group consisting of -N(CH3)2, NO2, OCH3, a hydrogen atom, preferably R 3 is a hydrogen atom and R 4 is chosen from the group consisting of: -CHO, CH2NH2, preferably, said second starting reagent is chosen from: benzaldehyde or benzylamine; and / or * a compound of formula (III) R5 -CHO (Formula III) in which R 5 is chosen from a linear or branched hydrocarbon chain comprising from 1 to 19 carbon atoms.

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

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

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

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