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KR-20260065798-A - C-glycoside synthesis method

KR20260065798AKR 20260065798 AKR20260065798 AKR 20260065798AKR-20260065798-A

Abstract

The present invention relates to a method for synthesizing at least one C-glycoside, the method comprising the steps of: (A) introducing into a first mechanochemical reactor, separately or in advance, at least one sugar in the form of D- and/or L-pyranose and/or furanose—said that the sugar essentially has at least one hydroxyl functional group at a free anomeric position—a first reagent which is a β-diketone, and a base to form a first initial mixture; (B1) grinding the first mixture once in the first mechanochemical reactor at a temperature of 20°C or higher for a residence time of 6 hours or less to form a C-glycoside ketone; and (C) recovering a final mixture at the outlet of the first mechanochemical reactor. The present invention also relates to the use of a mechanochemical reactor for synthesizing the C-glycoside or the C-glycoside derivative, wherein the C-glycoside derivative comprises the at least one C-glycoside.

Inventors

  • 티엘, 줄리엔
  • 말파르티다, 이레느
  • 레르, 발렌틴
  • 할로우미, 사미
  • 라코스테, 프랑수아
  • 와두아시, 안느
  • 조스, 솔렌
  • 보파랭, 에스텔

Assignees

  • 디아질 에스에이
  • 유니베흐시티 아미앵 피카르디 줄 베흔

Dates

Publication Date
20260511
Application Date
20240712
Priority Date
20230713

Claims (17)

  1. A method for synthesizing at least one C-glycoside comprising the following consecutive steps: Step (A) of introducing a first reagent, which is a pyranose and/or furanose form and at least one sugar of the D and/or L series—said to essentially have at least one hydroxyl functional group at a free anomeric position—a β-diketone, and a base into a first mechanochemical reactor, either separately or in advance, to form a first initial mixture; Step (B1) of forming a C-glycoside ketone by first grinding the first initial mixture at least once in the first mechanochemical reactor at a temperature of 20°C or higher for a residence time of 6 hours or less; Step (C) of recovering a final product containing at least one C-glycoside at the outlet of the first mechanochemical reactor.
  2. A synthesis method according to claim 1, wherein the first initial mixture comprises water as LAG.
  3. A synthesis method according to claim 1, wherein at least one first grinding of the initial mixture is performed at a temperature of 30°C to 120°C, particularly at a temperature of 40°C to 90°C.
  4. A synthesis method according to claim 1 or 2, wherein the residence time of the first initial mixture in the first mechanochemical reactor is 4 hours or less, particularly 1 minute to 3 hours.
  5. A synthesis method according to any one of claims 1 to 4, wherein the at least one sugar is selected from monosaccharides, oligosaccharides containing 2 to 10 sugar units, polysaccharides containing 11 or more sugar units, and mixtures thereof.
  6. In claim 5, the monosaccharide is selected from D-glucose, D-galactose, D-mannose, D-xylose, D-rixos, L-fucose, L-arabinose, D-ribose, L-rhamnose, D-glucuronic acid, D-galacturonic acid, D- or L-iduronic acid, N-acetyl-D-glucosamine, and N-acetyl-D-galactosamine, preferably D-glucose, D-xylose, N-acetyl-D-glucosamine or L-fucose, and most preferably D-xylose. or The above oligosaccharides are oligosaccharides comprising up to six sugar units, for example, disaccharides formed by combining a uronic acid selected from D-maltose, D-lactose, D-cellobiose, melivise, D-maltotriose, D- or L-iduronic acid or D-glucuronic acid with a hexosamine selected from D-galactosamine, D-glucosamine, N-acetyl-D-galactosamine, N-acetyl-D-glucosamine, or an oligosaccharide comprising at least one xylose, preferably selected from xylobiose, methyl-β-xylobioside, xylotriose, xylotetrase, xylopentaose, and xylohexase, and preferably selected from xylobiose comprising two xylose molecules connected by a beta-1,4 linkage; or The above polysaccharide is selected from cellulose, starch, amylose, amylopectin, galacturonan, glucuronan, chitin, chitosan, dextran, glucan, mannan, galactan, alginate, pectin, pullulan, or mixtures thereof; And a synthesis method that is a mixture of these.
  7. A synthesis method according to any one of claims 1 to 6, wherein the first starting reagent is a β-diketone and has the following chemical formula (I): R 1 -CO-CH 2 -CO-R 2 (Chemical Formula I), Here, R1 and R2 independently represent a linear or branched, saturated or unsaturated, alkyl chain or hydrofluoroalkyl chain, cycloalkyl, cycloperfluoroalkyl or cyclohydrofluoroalkyl ring, or phenyl or benzyl radical each comprising 1 to 18 carbon atoms, said chain, ring or radical may be selectively interrupted by one or more heteroatoms selected from oxygen, sulfur and nitrogen, and preferably R1 represents an alkyl group such as a methyl group.
  8. A synthesis method according to any one of claims 1 to 7, wherein during step (A), the concentration of the at least one sugar in the first initial mixture is 100 g/L or more, preferably in the range of 100 g/L to 10,000 g/L, particularly in the range of 200 g/L to 3,000 g/L, and typically in the range of 450 g/L to 2,800 g/L.
  9. A synthesis method according to any one of claims 1 to 8, wherein during step (A), the amount of the first starting reagent per 1 equivalent of the at least one sugar is in the range of 0.75 to 5 equivalents, preferably in the range of 1 to 2 equivalents, and typically in the range of 1 to 1.2 equivalents.
  10. A synthesis method according to any one of claims 1 to 9, wherein during step (A), the amount of base per 1 equivalent of the at least one sugar is in the range of 1 to 4 equivalents, preferably in the range of 1.2 to 3 equivalents, and generally in the range of 1.2 to 2.5 equivalents.
  11. In any one of paragraphs 1 through 10, A synthesis method comprising, at least, a second grinding (B2) performed in a first mechanochemical reactor after step (B1) or in a second mechanochemical reactor different from the first mechanochemical reactor after step (C), from a second initial mixture comprising at least a second starting reagent and a previously formed C-glycoside ketone—so-called C-glycoside ketone starting reagent—at the end of step (B1) to functionalize the starting C-glycoside ketone and obtain another C-glycoside.
  12. A synthesis method according to claim 11, wherein the second grinding (B2) is performed immediately after step (B1) and in the first mechanochemical reactor.
  13. In paragraph 11 or 12, the above functionalization reaction is, - Aldolation-crotonization reaction to obtain C-glycosides having α,β unsaturated ketone functional groups such as C-glycosides-enones, and - A synthesis method selected from the addition reaction of an O-, N-, S-, C-nucleophile, preferably an aliphatic or aromatic N-nucleophile, to obtain a C-glycoside imine.
  14. A synthesis method according to any one of claims 11 to 13, wherein during step (B2), the second starting reagent is selected from the following: - Compound of chemical formula (II) Chemical formula (II) Here, R3 is selected from the group consisting of -N( CH3 ) 2 , NO2 , OCH3 , and a hydrogen atom, preferably R3 is a hydrogen atom, and R4 is selected from the group consisting of -CHO and CH2NH2 ; preferably, the second starting reagent is selected from benzaldehyde or benzylamine; and/or - Compound of chemical formula (III) R 5 -CHO (Chemical Formula III) Here, R 5 is selected from linear or branched hydrocarbon chains having 1 to 19 carbon atoms.
  15. A synthesis method comprising, in any one of claims 1 to 14, a step (D) of neutralizing the final product.
  16. In any one of claims 1 to 14, the first or second mechanochemical reactor is, - Planetary ball mill; - Vibration mill; - 3D wet mill with or without balls; - A synthesis method independently selected from among extruders.
  17. Use of a first and/or second mechanochemical reactor for carrying out a method for synthesizing at least one C-glycoside according to any one of claims 1 to 16.

Description

C-glycoside synthesis method The present invention relates to a method for synthesizing a C-glycoside that may include a ketone functional group or a chemical functional group. In particular, the present invention relates to a method for synthesizing a C-glycoside that may include at least one ketone functional group or at least one other chemical functional group, which is carried out through mixing/grinding (i.e., grinding, fine grinding, or even extrusion) in a single specific mechanochemical reactor, such as a three-dimensional wet mill. In addition, the present invention relates to the use of said mechanochemical reactor for synthesizing at least one C-glycoside through one or generally several sequential reactions without the need to remove the reaction medium(s) from the mechanochemical reactor. Carbohydrates, known as sugars having the general formula C n (H 2 O) n , are an abundant family of natural compounds existing in various forms such as monomers, oligomers, and polymers. These biological resources are the subject of intensive research, particularly due to the many applications of their derivatives, including C-glycosides. For example, C-β-D-xylopyranoside-2-(S)-hydroxypropane (Pro-Xylane®), developed by L'OREAL, is a C-glycoside derivative prepared from D-xylose and is known as an anti-aging molecule that promotes the biosynthesis of glycosaminoglycans of interest. Generally, C-glycosides are a class of compounds in which a carbohydrate is connected to an aglycone or another carbohydrate via a C-C bond instead of the typical C-O glycoside bond. Due to this structural modification, C-glycosides are very stable in both chemical and enzymatic hydrolysis. Various methodologies have been developed to produce C-glycosides. The preparation of these compounds mostly involves multi-step reactions that protect the hydroxyl group of the sugar and activate the anomeric position by introducing or oxidizing a suitable activator. This conversion process consumes large amounts of reagents and organic solvents and, in particular, affects the E factor (i.e., the mass ratio of waste to desired product). In practice, the synthesis reaction is typically carried out in H₂O-organic solvents (methanol (MeOH), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (CH₃CN), dimethyl sulfoxide (DMSO), ethanol (EtOH), etc.) by reacting the protected sugar (ose, monosaccharide) with an excess of pentane -2,4 -dione (i.e., acetylacetone) (sugar/acetylacetone molar ratio = 1/2 ) and an excess of base in the reaction medium (sugar/base molar ratio = 1/15) for about 48 hours. The reaction proceeds in the reaction solvent with the sugars/acetylacetone molar ratio present in excess at 1/15. The reaction may be heated (e.g., up to 90°C) or not heated ( Schoenenberger , B.; Summermatter, W.; Ganter, C., Enantio selective Synthesis of Pseudomonic Acids. I. Synthesis of Key Intermediates , Helvetica Chimica Acta 1982, 65 (7), 2333-2337 or Howard , S.; Withers, SG, Bromoketone C- glycosides, a new class of beta-glucanase inactivators J. Am. Chem. Soc. 1998, 120, 10326-10331). The existing synthesis method for C-glycosides described above has several disadvantages. This method proceeds in a batch manner, making it non-continuous, complex to execute, time-consuming, and not environmentally friendly. In particular, the two papers mentioned above describe a multi-step synthesis method involving the protection/deprotection of sugar hydroxyl groups to obtain C-glycoside derivatives, using harsh conditions and/or toxic reagents in the process. Schoenenberger et al. first protect D-ribose with an acetal, then proceed with the Wittig reaction in refluxed acetonitrile; and treat the intermediate acyclic intermediate derivative with MeONa to obtain a mixture of acetylated C-riboside and non-acetylated C-riboside. Howard et al. used tetrabenzylated allyl-β-C-glucoside as a starting material to carry out an epoxidation reaction with mCPBA, followed by reduction with DIBAL-H, and finally a Jones oxidation reaction using chromic acid. The β-C-glucoside of interest is finally obtained after deprotecting the benzyl group. These synthesis methods are not environmentally suitable. The literature by Lubineau et al. (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 β-D-C-glycosidic ketones from pentane-2,4-diones with unprotected ose groups via Knoevenagel condensation in an aqueous alkaline medium rather than an organic solvent. The synthesis reaction proposed by Lubineau et al. is shown in Fig. 1. The Knoebenagel condensation reaction from pentane-2,4-dione enables the formation of intermediate compound 11 shown in FIG. 1, which occurs via the nucleophilic addition of the anion of the in situ-generated pentane-2,4-dione to the aldehyde of the sugar, leading to a β-elimination reaction of water to form enone compo