Process for the preparation of raspberry ketone

Abstract

The invention relates to a process for the preparation of raspberry ketone comprising the step of condensing phenol with glyoxylic acid.

Description

[0001] This case is a divisional application of the patent application filed on December 1, 2021, with application number 2021800812163 and invention title "Method for preparing raspberry ketone". Technical Field

[0002] This invention relates to a method for preparing frambione, comprising the step of condensing phenol with glyoxylic acid. Background Technology

[0003] Raspberry ketone, or 4-(4-hydroxyphenyl)-2-butanone, is the main aromatic compound in raspberries, but it is also found in cranberries or blackberries.

[0004] Raspberry ketones are used in perfumes, cosmetics, and the agricultural industry to produce fruity flavors.

[0005] This natural aromatic compound can be extracted from the fruit at a rate of 1 to 4 mg per kilogram of raspberry. Given the very low abundance of this aromatic compound in the fruit, synthetic methods have been developed, particularly those involving the following: - Alkylation of phenol in the presence of butenone, as in FR 1227595 or Guo Hui et al. Bulletin of the Korean Chemical Society [Korean Chemical Society Bulletin], 2013, 34( 9 As described in 2594-2596, - Phenol is condensed in the presence of 4-hydroxy-2-butanone, as described in US 2011 / 257439, DE 2145308, CN104355977 or CN 104496778. 4-Hydroxy-2-butanone is prepared by the condensation of acetone with formaldehyde; - Phenol is condensed in the presence of 2-acetyl-2-hydroxymethylethyl acetate, as described in FR 2221433. The compound 2-acetyl-2-hydroxymethylethyl acetate is prepared from formaldehyde and ethyl acetoacetate; - Condensate phenol with 1,3-dichloro-2-butene, as described in JP 01242549; or - Demethylation of anisylacetone in the presence of hydrobromic acid, as described in CN 104193607.

[0006] These methods have drawbacks, especially the use of compounds that are known to be harmless: but-2-en-1-one, formaldehyde, or hydrobromic acid.

[0007] This invention aims to produce raspberry ketones via a novel route using non-toxic and low-cost starting materials. Advantageously, this method allows for the production of new compounds: natural raspberry ketones, and advantageously uses reagents of natural origin. Compared with prior art methods, this method advantageously uses milder operating conditions (especially in terms of temperature or pressure). Summary of the Invention

[0008] The first subject of the present invention relates to a method for preparing raspberry ketone, comprising the step (a) of condensing phenol with glyoxylic acid.

[0009] The present invention also relates to raspberry ketones that can be obtained according to the method of the present invention.

[0010] The present invention also relates to raspberry ketones with a bio-based carbon content greater than or equal to 50% and strictly less than 100%.

[0011] This invention relates to 13 The carbon isotope deviation is between -27‰ and -15‰, with raspberry ketone having a bio-based carbon content greater than or equal to 50% being preferred.

[0012] The present invention also relates to the use of raspberry ketone according to the invention as a flavoring agent or spice.

[0013] Finally, the present invention relates to a composition comprising raspberry ketone according to the present invention.

[0014] Figure 1 Numbering of raspberry ketone positions used to characterize the D / H ratio Detailed Implementation

[0015] In the context of this invention, and unless otherwise stated, the expression "between..." includes limit values. Unless otherwise stated, percentages and ppm are percentages and ppm by mass.

[0016] In the context of this invention, and unless otherwise stated, the term "ppm" means "parts per million". This unit represents a mass fraction: 1 ppm = 1 mg / kg.

[0017] In the context of this invention, the term "bio-based source" means a product that is wholly or primarily composed of biological products or of renewable agricultural (including plant, animal, and marine) or forestry materials.

[0018] In the context of this invention, the term "bio-based carbon" or "biosourced carbon" refers to carbon from renewable sources in the natural environment in balance with the atmosphere, such as carbon from living agriculture, plants, animals, fungi, microorganisms, marine life, or forestry. Bio-based carbon content is typically assessed using carbon-14 dating (also known as carbon dating or radiocarbon dating). Furthermore, in this invention, the term "bio-based carbon content" refers to the molar ratio of bio-based carbon to total carbon in a compound or product. Bio-based carbon content can preferably be measured via liquid scintillation counting at a rate of disintegration per gram of carbon per minute (or 10 dpm / gC) according to the standard test method ASTM D6866-16. 14 The method for measuring the decay process of C (carbon-14) is described. The American standard test method ASTM D6866 is considered equivalent to standard ISO 16620-2. According to ASTM D6866, the test method can preferably utilize AMS (accelerator mass spectrometry) technology. 13 CIRMS (isotope ratio mass spectrometry) is used to quantify the bio-based content of a given product.

[0019] Hydrogen and carbon atoms and their stable isotopes (deuterium and carbon, respectively) 13 C) Naturally coexisting. D / H and 13 C / 12 The quantity and ratio of carbon are influenced by several factors, especially the environment in which natural products are produced. The isotopic fingerprint of a product provides information about its origin, particularly whether it is of natural or fossil origin. 2 The H-SNIF-NMR method measures the deuterium / hydrogen ratio at each site of the molecule. 13 C-SNIF-NMR method to measure each site of the molecule 13 C / 12 C ratio.

[0020] The D / H ratio is measured by comparison with the international reference standard tetramethylurea (TMU). For example, this measurement can be performed in dioxane or in a dioxane / benzene mixture.

[0021] average 13 C isotope bias (δ) 13 C) was measured by isotope ratio mass spectrometry (IRMS) relative to the international reference standard PDB (pee bee belemnite).

[0022] Step (a): The method for preparing raspberry ketone includes step (a) of condensing phenol with glyoxylic acid, and can be represented according to the following scheme: Step (a) of the condensation of phenol with glyoxylic acid allows the formation of 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (compound I).

[0023] Step (a) can be carried out according to any method used for condensing aromatic derivatives with glyoxylic acid, especially as specifically described in WO 09 / 077383 or WO 2015 / 071431.

[0024] Phenol can be bio-based or non-bio-based.

[0025] According to one embodiment of the invention, phenol with a bio-based carbon content greater than 50% is also referred to as "bio-based phenol". The bio-based carbon content of the bio-based phenol according to the invention can be higher than 60%, preferably between 75% and 100%, more preferably between 90% and 100%, more preferably between 95% and 100%, more preferably between 98% and 100%, and even more preferably between 99% and 100%. Bio-based phenol is a commercial product. It can be obtained naturally from natural resources such as lignin (especially via various methods), from charcoal oil, from vegetable oil residues, or from sugars. Several biochemical methods are known. For example, US 2013 / 0232852 can be mentioned, which describes a method for the biorefining of lignin biomass. EP 2639295 can also be mentioned, which describes a biochemical method for producing phenol from sugars.

[0026] Given the bio-based origin of phenol, it may contain certain impurities. The nature of the impurities in bio-based phenol differs from that in fossil-derived phenol. Furthermore, these impurities may be specific, depending on the source of the phenol and its preparation method. Generally, the purity of bio-based phenol is greater than or equal to 99%. Generally, the total impurity content in bio-based phenol is less than or equal to 1% and greater than or equal to 0.5%. Generally, the content of each impurity in bio-based phenol is between 0.005% and 0.1%, preferably between 0.01% and 0.08%.

[0027] Generally speaking, the average δ of bio-based phenols 13 The C isotope deviation is between -33‰ and -20‰, preferably between -30‰ and -25‰, and very preferably between -30‰ and -27‰.

[0028] Glyoxylic acid can be bio-based or non-bio-based.

[0029] According to one embodiment of the invention, glyoxylic acid with a bio-based carbon content greater than 50% is also referred to as "bio-based glyoxylic acid". The bio-based carbon content of the bio-based glyoxylic acid according to the invention can be higher than 60%, preferably between 75% and 100%, more preferably between 90% and 100%, more preferably between 95% and 100%, more preferably between 98% and 100%, and even more preferably between 99% and 100%. Bio-based glyoxylic acid and non-bio-based glyoxylic acid can be purchased from several manufacturers. Certain methods for producing bio-based glyoxylic acid are described in the prior art. In particular, various biochemical methods are available. For example, US 5219745 describes an industrially advantageous method for the biochemical production of glyoxylic acid. Alternatively, bio-based glyoxylic acid can be produced from bio-based starting materials (such as bio-based ethanol, or bio-based glycerol or bio-based ethylene glycol) according to well-known industrial methods (see, for example, Ullmann's Encyclopedia of Industrial Chemistry, G. MATTIODA and Y. CHRISTIDIS, Vol. 17, pp. 89-92, 2012, "glyoxylic acid").

[0030] Because of its bio-based origin, glyoxylic acid may contain certain impurities. The nature of these impurities in bio-based glyoxylic acid differs from that in fossil-derived glyoxylic acid. Furthermore, these impurities may be specific, depending on the source of the glyoxylic acid and its preparation method.

[0031] According to a particular aspect, the average value of the bio-based glyoxylic acid used in this invention is... 13 The C isotope deviation is generally between -33‰ and -7‰, preferably between -31‰ and -9‰, more preferably between -30‰ and -10‰, and very preferably between -31‰ and -25‰.

[0032] According to another specific aspect, the average value of bio-based glyoxylic acid used in the context of this invention is... 13 The carbon isotope deviation is generally between -7‰ and -3‰, and preferably between -6‰ and -5‰.

[0033] The condensation reaction between phenol and glyoxylic acid allows for the synthesis of the corresponding condensation product, p-hydroxymandelic acid. This condensation step may produce certain impurities, namely o-hydroxymandelic acid (compound II) and dimandelic acid derivatives (compound III). Other phenolic impurities may react during the condensation step.

[0034] According to one aspect, the bio-based carbon content of the compound (I) obtained at the end of step (a) is greater than or equal to 50%, preferably greater than or equal to 70%, more preferably greater than or equal to 75%, and less than or equal to 100%.

[0035] The molar ratio between phenol and glyoxylic acid can be between 1.0 and 4.0, preferably between 1.2 and 2.2.

[0036] The condensation reaction can be carried out in stirred reactors connected in series. According to one variant, the reaction is carried out in a plug-flow reactor, optionally including a heat exchanger. For example, such an embodiment is described in patent application WO 09 / 077383. The condensation reaction between phenol and glyoxylic acid can be carried out in water in the presence of an alkali metal in a plug-flow reactor. It can also be carried out in a tubular reactor.

[0037] Advantageously, the condensation reaction can be catalyzed with quaternary ammonium hydroxide according to the reaction described in patent application EP 0 578 550.

[0038] According to one embodiment of the invention, phenol and glyoxylic acid are reacted in the presence of a base (preferably a mineral base or organic base, more preferably an alkali metal), and even more preferably in the presence of NaOH, KOH, lime, or K₂CO₃. Sodium hydroxide may be preferred for economic reasons. The alkali metal hydroxide can be used in solution. In this respect, the alkali metal hydroxide solution can have a concentration between 10% by weight and 50% by weight. The amount of alkali metal hydroxide introduced into the reaction medium takes into account the amount required to salt the hydroxyl functional group of phenol and the carboxylic acid functional group of glyoxylic acid. According to this variant, phenol is in the form of a phenolate salt and the condensation product is a mandelate compound. Generally, the amount of alkali metal hydroxide is between 80% and 120% of the stoichiometric amount.

[0039] Next, the phenolate reacts with glyoxylic acid to form the corresponding para-mandelate. These two reaction steps for preparing the glyoxylic acid and phenolate can be carried out in two separate steps. Alternatively, the glyoxylic acid can be directly contacted with the phenolate in the presence of a base.

[0040] One possible variation is to carry out the reaction in the presence of a dicarboxylic acid catalyst (preferably oxalic acid), as described in International Patent Application WO 99 / 65853. The amount of catalyst used, expressed as the ratio of the moles of catalyst to the moles of glyoxylic acid, can advantageously be selected to be between 0.5% and 2.5%, and preferably between 1% and 2%.

[0041] According to one embodiment of the invention, phenol is mixed with an alkaline agent, and then the phenol is contacted with glyoxylic acid. Therefore, the method according to the invention may include a first step of contacting phenol with an aqueous solution of an alkali metal hydroxide, followed by contacting the resulting solution with glyoxylic acid. Advantageously, this embodiment allows for better control of the reaction temperature because the salting-out reaction of glyoxylic acid is exothermic.

[0042] According to another embodiment, the method according to the invention includes contacting glyoxylic acid with an aqueous solution of an alkali metal hydroxide in a first step, followed by contacting the resulting solution with phenol.

[0043] According to yet another embodiment, the method according to the invention includes, on the one hand, contacting phenol with an aqueous alkaline agent, and on the other hand, contacting glyoxylic acid with an aqueous alkaline agent, followed by contacting the two resulting solutions together.

[0044] These optional steps of contacting glyoxylic acid with an aqueous alkali metal hydroxide and / or contacting phenol with an alkaline agent can be carried out at temperatures between 10°C and 40°C, for example at 15°C or 35°C.

[0045] The resulting reaction mixture may have a viscosity between 0.5 mPa·s and 50 mPa·s at 20°C, and more preferably between 1.5 mPa·s and 3 mPa·s. According to the invention, this mixture is introduced into at least one reactor in which the condensation reaction occurs.

[0046] According to another embodiment of the invention, phenol is reacted with glyoxylic acid in the presence of no added acidic or basic compound. This embodiment is also described in WO 2015 / 071431.

[0047] This condensation step can be carried out in an aqueous medium. When using an aqueous medium, the concentration of phenol is preferably between 0.5 mol / L and 1.5 mol / L, and more particularly about 1 mol / L. Glyoxylic acid can be used as an aqueous solution with a concentration, for example, between 15 wt% and 70 wt%. A commercial solution with a concentration of about 50 wt% is preferred.

[0048] According to another embodiment of the invention, phenol is reacted with glyoxylic acid in the absence of any solvent, and the glyoxylic acid is glyoxylic acid monohydrate. This embodiment is also described in WO 2015 / 071431.

[0049] According to another embodiment of the invention, phenol is reacted with glyoxylic acid in the presence of a catalyst selected from the group consisting of transition metal complexes containing oxygen-containing ligands. The catalyst is preferably selected from the group consisting of: ferric acetate (II) (Fe(OAc)2), ferric acetate (III) (Fe(OAc)3), copper acetate (II) (Cu(OAc)2), ferric acetylacetone (II) (Fe(acac)2), ferric acetylacetone (III) (Fe(acac)3), copper acetylacetone (II) (Cu(acac)2), copper acetylacetone (III) (Cu(acac)3), and transition metal complexes containing glyoxylate ligands. This embodiment is also described in WO 2015 / 071431.

[0050] The operating conditions for this reaction can be set according to the reagents used and the type of reactor or reactor sequence.

[0051] The reaction temperature can be between 10°C and 90°C. According to one embodiment, the reaction temperature can be between 10°C and 20°C. According to another embodiment, the temperature can be between 30°C and 40°C. Furthermore, the temperature can be varied during the reaction. For example, the reaction can be carried out at a temperature between 10°C and 20°C for a certain period of time, and then the temperature can be increased to between 30°C and 50°C for a finishing stage.

[0052] The reaction can be carried out at atmospheric pressure, optionally in a controlled atmosphere of an inert gas (preferably nitrogen), or optionally a rare gas (especially argon). Nitrogen is preferred.

[0053] The total residence time of the reagent in continuous operation and the operation or cycle time in batch operation can vary greatly, from minutes to hours or even days, especially with changes in operating conditions, particularly with changes in reaction temperature. When the temperature is between 10°C and 20°C, the total residence time of the reagent can range from 10 hours to 100 hours. When the temperature is between 30°C and 50°C, the total residence time of the reagent can range from 30 minutes to 30 hours.

[0054] Following the condensation reaction, the resulting condensed compound can be separated from the reaction mixture using conventional separation techniques, particularly by crystallization or extraction with a suitable organic solvent. A neutralization step may be performed.

[0055] As a variant, the reaction mixture obtained after the condensation reaction can be used in its existing form. However, it is preferable to recover unreacted phenol. Since phenol is generally in excess relative to glyoxylic acid, it is advantageous to recover the unreacted phenol fraction from the recycling loop, for example, via a distilled water / phenol azeotrope. This excess reduces the likelihood of forming dimandelic acid-type compounds (i.e., compounds produced by the condensation of two glyoxylic acid molecules with one guaiacol molecule). As described in WO 2014 / 016146, unreacted phenol can be recovered by acidification. This involves adding a mineral acid (e.g., hydrochloric acid or sulfuric acid) to adjust the pH to between 5 and 7, and then extracting the unreacted phenol in an organic solvent (especially in ether or toluene). After extraction, the aqueous and organic phases can be separated.

[0056] Step (b): The method for preparing raspberry ketone may also include step (b) of decarboxylating the compound of formula (I) obtained at the end of step (a) to form the compound of formula (IV).

[0057] Step (b) is the step of oxidizing compound (I) according to the following scheme to form compound (IV) and releasing carbon dioxide: Furthermore, compounds (II) and (III) obtained from step (a) can also be oxidized under the same conditions to form compounds (V) and (VI).

[0058] Impurities contained in bio-based phenols that may have already reacted in step (a) are also easily oxidized under the conditions of step (b).

[0059] This oxidation can be carried out in an oxidizing atmosphere such as O2 or in air.

[0060] According to one variant, the reaction medium is an aqueous alkaline medium (preferably a mineral alkali and more preferably sodium hydroxide or potassium hydroxide) to form the corresponding phenol salt and to capture the released CO2 in the form of carbonate.

[0061] The reaction can be carried out continuously or in batches, for example, in a medium highly diluted with water.

[0062] This reaction can be catalyzed. The catalyst for this oxidation reaction can be selected from catalysts containing at least one metallic element selected from the group consisting of: copper, nickel, cobalt, iron, magnesium, and any mixture thereof. Examples of inorganic or organic copper compounds include, in particular, cuprous bromide and copper bromide; cuprous iodide; cuprous chloride and copper chloride; basic copper carbonate; cuprous nitrate and copper nitrate; cuprous sulfate and copper sulfate; cuprous sulfite; cuprous oxide and copper oxide; copper hydroxide; cuprous acetate and copper acetate; and copper trifluoromethanesulfonate. Specific examples of nickel derivatives may include nickel(II) halides, such as nickel(II) chloride, nickel(II) bromide, or nickel(II) iodide; nickel(II) sulfate; nickel(II) carbonate; nickel(II) hydroxide; salts of organic acids containing 1 to 18 carbon atoms, especially acetates or propionates; nickel(II) complexes, such as nickel(II) acetylacetonate, nickel(II) dichlorobis(triphenylphosphine) or nickel(II) dibromobis(bipyridine); and nickel(O) complexes, such as nickel(O)bis(1,5-cyclooctadiene) or nickel(O)bisdiphenylphosphine ethane. Examples of cobalt-based compounds that can be specifically mentioned are cobalt(II) halides and cobalt(III) halides, such as cobalt(II) chloride, cobalt(II) bromide, or cobalt(II) iodide, or cobalt(III) chloride, cobalt(III) bromide, or cobalt(III) iodide; cobalt(II) sulfate and cobalt(III) sulfate; cobalt(II) carbonate, basic cobalt(II) carbonate; cobalt(II) orthophosphate; cobalt(II) nitrate; cobalt(II) oxide and cobalt(III) oxide; cobalt(II) hydroxide and cobalt(III) hydroxide; salts of organic acids containing 1 to 18 carbon atoms, especially cobalt(II) acetate and cobalt(III) acetate or cobalt(II) propionate; cobalt(II) complexes, such as hexaamine cobalt(II) chloride or hexaamine cobalt(III) chloride, hexaamine cobalt(II) sulfate or hexaamine cobalt(III) sulfate, pentamine cobalt(III) chloride or triethylenediamine cobalt(III) chloride. Iron-based catalytic systems, generally in the form of oxides, hydroxides, or salts, can also be used, such as ferric chloride(II) and ferric chloride(III), ferric bromide(II) and ferric bromide(III), ferric iodide(II) and ferric iodide(III), or ferric fluoride(II) and ferric fluoride(III); ferric sulfate(II) and ferric sulfate(III); ferric nitrate(II) and ferric nitrate(III); or ferric oxide(II) and ferric oxide(III). Ferric acetate(II) (Fe(OAc)2), ferric acetate(III) (Fe(OAc)3), ferric acetylacetone(II) (Fe(acac)2), or ferric acetylacetone(III) (Fe(acac)3) can also be used. The reaction can also be catalyzed using manganese-based catalytic systems, such as manganese carbonate(II) or manganese acetate(III). This oxidation reaction can be catalyzed, for example, by a catalytic system containing two metal elements selected from the group to form: copper, nickel, cobalt, iron, magnesium, and any mixture thereof.The teachings of WO 2008 / 148760 can be applied to the preparation of compounds (IV). This invention particularly covers the reactions described in patent application WO08 / 148760.

[0063] In the first stage, the condensed compound (IV) obtained at the end of step (a) is reacted with a base (preferably sodium hydroxide) to salt the phenolic salt functional groups of the condensed compound. Next, oxidation in an oxidizing medium (preferably air) produces compound (IV) and CO2 (captured as a carbonate). At the end of the oxidation reaction, compound (IV) in its salted form, i.e., having hydroxyl groups in a salted (ionic) form, is obtained, along with various impurities including tar. In subsequent steps, the salted compound (IV) in the reaction medium is acidified with a strong acid (e.g., sulfuric acid).

[0064] According to another embodiment of the invention, the oxidation reaction can be carried out in the absence of any added acidic or basic compounds. This embodiment is also described in WO 2015 / 071431.

[0065] According to one aspect, the bio-based carbon content of the compound (IV) obtained at the end of step (b) is greater than or equal to 50%, preferably greater than or equal to 70%, more preferably greater than or equal to 75%, and less than or equal to 100%.

[0066] Step (c): A method for preparing raspberry ketone may include step (c) of condensing the compound of formula (IV) obtained at the end of step (b) with acetone to form the compound of formula (VII).

[0067] Step (c) involves condensing the compound of formula (IV) obtained at the end of step (b) with acetone, followed by dehydration, to form the compound of formula (VII).

[0068] According to one aspect, the acetone used in step (c) is bio-based acetone. This bio-based acetone has a bio-based carbon content between 75% and 100%, more preferably between 90% and 100%, more preferably between 95% and 100%, more preferably between 98% and 100%, and more preferably between 99% and 100%. Bio-based acetone is a commercial product. It can be obtained naturally from natural resources, such as through fermentation of sugars from corn residues (especially residues from the sugar industry). Several biochemical methods are known, such as Jones, DT, and Woods, DR (1986). Microbiol. Rev.[Microbiology Review] 50: 484-524, or as described in EP 2875139.

[0069] Given the bio-based origins of acetone and its production process, it may contain certain impurities, particularly methanol, isopropanol, or aldehydes. These impurities may be specific, depending on the source of the acetone.

[0070] The average value of the bio-based acetone used in this invention 13 The carbon isotope deviation is generally between -10‰ and -2‰, preferably between -8‰ and -4‰.

[0071] The nature of impurities in bio-based acetone differs from that in fossil-based acetone. Furthermore, these impurities may be specific, depending on the source of the acetone and its preparation method. Generally, bio-based acetone has a purity greater than or equal to 99%. Generally, the total impurity content in bio-based acetone is less than or equal to 1% and greater than or equal to 0.5%. Generally, the content of each impurity in bio-based acetone is between 0.005% and 0.1%, preferably between 0.01% and 0.08%.

[0072] Generally, step (c) is carried out in the presence of at least 1 equivalent of acetone, preferably no more than 5 equivalents of acetone, such as 2 equivalents of acetone.

[0073] Step (c) can be carried out in the presence of a base or an acid.

[0074] According to the first aspect, step (c) is carried out in the presence of a base. According to one particular aspect, the base may be present in a catalytic amount. According to another aspect, step (c) is carried out in the presence of 1 equivalent of a base. Generally, the amount of base is less than or equal to 2 equivalents.

[0075] The alkali used can be a mineral alkali, such as KOH or NaOH. The alkali can be in the form of an aqueous solution with a concentration between 10% and 50% by weight, preferably between 15% and 25% by weight.

[0076] The alkali used can also be an alkaline solid of alkali metal, alkaline earth metal, rare earth metal or transition metal, such as preferably oxides, hydroxides, carbonates or hydrooxycarbonates selected from the group consisting of: Li2O, Na2O, Al2O3, K2O, Cs2O, BaO, MgO, BaCO3, CeO2 and La2O3.

[0077] The alkali used can also be anion exchange resin with alkaline properties.

[0078] Generally, the reaction is maintained at a temperature between 10°C and 60°C, preferably between 20°C and 50°C, and most preferably between 25°C and 40°C. The reaction is generally carried out in a solvent preferably selected from water, acetone, alcohol, or mixtures thereof. Preferably, the alcohol is selected from methanol, ethanol, and isopropanol. This example is particularly described in CN 1097729.

[0079] According to another aspect, step (c) is carried out in the presence of an acid. Step (c) can be carried out in a mixture comprising water, an alcohol (preferably ethanol), acetone, and an acid, or in the presence of a catalytic amount of acid. According to one aspect, the amount of acid relative to the amount of compound (IV) is generally less than or equal to 1 equivalent, preferably less than or equal to 0.8 equivalents, and more preferably less than or equal to 0.5 equivalents. Generally, the amount of acid is greater than or equal to 0.01 equivalents, preferably greater than or equal to 0.1 equivalents. The solvent for step (c) can be selected from water, acetone, alcohol, acetic acid, or mixtures thereof. According to another aspect, the reaction is carried out in a water / acid mixture; generally, the volume ratio of water to acid is between 1:1 and 5:1. The acid used can also be a cation exchange resin with acidic properties.

[0080] Generally, the reaction is maintained at a temperature between 10°C and 60°C, preferably between 20°C and 50°C, and most preferably between 25°C and 40°C. The acid is generally a strong acid, preferably selected from acids with a pKa less than or equal to 2, such as sulfuric acid, trifluoromethanesulfonic acid, hydrochloric acid, or hydrobromic acid.

[0081] According to another aspect, step (c) can be carried out in the presence of an amino acid, preferably selected from proline, aziridine-2-carboxylic acid, piperidine-2-carboxylic acid, 4-hydroxypyrrolidine-2-carboxylic acid, pyrrolidine-2-carboxamide, thiazolidin-4-carboxylic acid, and 4-acetoxypyrrolidine-2-carboxylic acid. The amount of amino acid is generally between 15% and 40% by volume. The solvent is generally a mixture of DMSO and acetone. These conditions are described in particular in... J. Am. Chem. Soc. [Journal of the American Chemical Society] 2000, 122 (10), 2395. However, contrary to the description in the aforementioned literature, the reaction allows for the formation of primarily α,β-unsaturated ketones.

[0082] Advantageously, the bio-based carbon content of the compound (VII) obtained at the end of step (c) is greater than or equal to 50%, preferably greater than or equal to 70%, more preferably greater than or equal to 75%, and less than or equal to 100%.

[0083] Depending on the specific aspect, the compound (VII) obtained at the end of step (c) is recovered in a salting form.

[0084] Step (d): The method for preparing raspberry ketone may include step (d) of hydrogenating the compound of formula (VII) obtained at the end of step (c) in a protonated or salted form.

[0085] Step (d) is a hydrogenation step that forms raspberry ketone (VIII) from the compound of formula (VII) obtained at the end of step (c).

[0086] According to one aspect of the invention, step (d) is carried out in the presence of a reducing agent, with or without heterogeneous catalysis.

[0087] Preferably, step (d) is carried out in the presence of a metal-based catalyst, which is preferably selected from Pd-based catalysts, Pt-based catalysts, Ni-based catalysts, Ru-based catalysts and Rh-based catalysts, such as Pd / C, Pt / alumina or Raney nickel.

[0088] The amount of catalyst is generally greater than or equal to 0.1% by weight, preferably greater than or equal to 0.5% by weight, and less than or equal to 25% by weight, preferably less than or equal to 20% by weight.

[0089] Step (d) is generally carried out in the presence of a reducing agent; in particular, the reducing agent may be selected from, for example... Org. Biomol. Chem. [Organic and Biomolecular Chemistry] 2015, 13 The dihydrogen, phosphite, and hypophosphite derivatives described in 7879-7906. The reducing agent can be selected from HCO2(NH4), NaH2PO2, Na2HPO3, and HCO2H.

[0090] The amount of reducing agent relative to the amount of compound of formula (VII) is generally greater than or equal to 1 equivalent, preferably greater than or equal to 1.5 equivalents, and less than or equal to 10 equivalents, preferably less than or equal to 7 equivalents, and very preferably less than or equal to 5 equivalents.

[0091] Generally, the solvent can be selected from the group consisting of water, alcohol or acetic acid and mixtures thereof; in particular, the solvent can be water, methanol, ethanol, isopropanol, acetic acid or mixtures thereof.

[0092] Depending on certain aspects, step (d) can be carried out in the presence of a base (preferably a strong base, and very preferably a non-nucleophilic strong base). Preferably, the base can be selected from tertiary amines, such as triethylamine.

[0093] Step (d) is generally performed at a temperature greater than or equal to 25°C, preferably greater than or equal to 30°C, more preferably greater than 40°C, and very preferably greater than 50°C. Generally, the temperature of step (d) is less than or equal to 190°C, preferably less than or equal to 175°C, and very preferably less than or equal to 150°C. Depending on a particular aspect, step (d) is performed at a temperature between 25°C and 100°C.

[0094] Step (d) can be performed at atmospheric pressure; alternatively, step (d) can be performed at autogenous pressure.

[0095] According to another aspect, step (d) can be carried out by biochemical transformation; in particular, the conversion of the compound of formula (VII) to the raspberry ketone of formula (VIII) can be carried out by means of microorganisms with olefin reductase activity, such as in GB 2416769 or in Journal of Molecular Catalysis B : Enzymatic [Journal of Molecular Catalysis B:] [Enzyme] As described in (1998), 4(5-6), 289-293.

[0096] According to a particular aspect of the invention, steps (c) and (d) can be performed without separating the compound of formula (VII). Steps (c) and (d) can be performed in a "one-pot" manner.

[0097] According to another aspect, steps (c) and (d) can be carried out without separating the compound of formula (VII) and can be carried out by heterogeneous catalysis, especially in the presence of a resin, preferably an acidic resin. This embodiment is particularly described in ACS Omega [American Chemical Society Omega] 2020, 5 , 14291-14296.

[0098] According to another aspect, steps (c) and (d) can be carried out without separating the compound of formula (VII) and can be carried out by acid catalysis in the presence of a reducing agent and a metal-based catalyst. Preferably, the metal-based catalyst is selected from Pd-based catalysts, Pt-based catalysts, Ni-based catalysts, Ru-based catalysts, and Rh-based catalysts, such as Pd / C or Raney nickel. The reducing agent is generally selected from NaH2PO2, HCO2H, and NaHPO2. The catalyst is generally a strong acid, such as hydrochloric acid or sulfuric acid. Generally, the solvent can be selected from the group consisting of water, alcohols, or acetic acid and mixtures thereof; in particular, the solvent can be water, methanol, ethanol, isopropanol, acetic acid, or mixtures thereof.

[0099] Advantageously, the compound (VIII) obtained at the end of step (d) has a bio-based carbon content of 50% or more, preferably 70% or more, more preferably 75% or more and less than or equal to 100%.

[0100] In a second aspect, the present invention relates to a method for preparing raspberry ketone from 4-hydroxybenzyl alcohol and acetone. This preparation method can be represented by the following scheme: 4-Hydroxybenzyl alcohol is a commercial product; in particular, this commercial product may be suitable for the agricultural products industry. 4-Hydroxybenzyl alcohol can be of bio-based or non-bio-based origin. 4-Hydroxybenzyl alcohol can also be obtained by reducing the aldehyde (IV) obtained at the end of step (b). Advantageously, the bio-based carbon content of 4-hydroxybenzyl alcohol is greater than or equal to 60%, preferably greater than or equal to 70%, most preferably greater than or equal to 75%, and less than or equal to 100%.

[0101] Acetone may be of bio-based origin, as described previously in step (c).

[0102] Generally, the condensation reaction of the compound of formula (IX) with acetone is carried out in an alkaline medium. The base used can be selected from NaOH, KOH, and K3PO4. The amount of base relative to the compound of formula (IX) is generally greater than or equal to 1 equivalent, preferably greater than or equal to 1.1 equivalents, and more preferably greater than or equal to 1.5 equivalents. Generally, the amount of base relative to the compound of formula (IX) is less than or equal to 5 equivalents, preferably less than or equal to 4 equivalents, and very preferably less than or equal to 3 equivalents.

[0103] Preferably, the condensation reaction of compound (IX) with acetone is carried out in the presence of a metal-based catalyst, which is preferably selected from Pd-based catalysts, Pt-based catalysts, Ni-based catalysts, Ru-based catalysts and Rh-based catalysts, such as Pd / C or Raney nickel.

[0104] The amount of catalyst is generally greater than or equal to 0.1% by weight, preferably greater than or equal to 0.5% by weight, and less than or equal to 25% by weight, preferably less than or equal to 20% by weight.

[0105] Generally, the solvent can be selected from the group consisting of water, alcohol, acetone, dioxane, and mixtures thereof; in particular, the solvent can be water, methanol, ethanol, isopropanol, acetone, dioxane, or mixtures thereof.

[0106] A third aspect of the invention relates to raspberry ketones obtainable by the method of the invention, particularly bio-based raspberry ketones obtainable by the method of the invention.

[0107] Advantageously, the compound (VIII) obtained at the end of the condensation step of the compound of formula (IX) and acetone has a bio-based carbon content of 50% or more, preferably 70% or more, more preferably 75% or more and less than or equal to 100%.

[0108] The fourth aspect of the invention covers raspberry ketones with a bio-based carbon content of 50% or more, preferably 75% or more and strictly less than 100%.

[0109] The present invention also covers a raspberry ketone, characterized by an average 13 The C isotope deviation is between -27‰ and -15‰, preferably between -23‰ and -15‰, more preferably between -22‰ and -15‰, more preferably between -23‰ and -18‰, more preferably between -22‰ and -18‰, and very preferably between -21‰ and -19‰.

[0110] Generally, the bio-based carbon content of the raspberry ketone of the present invention is greater than or equal to 50%, preferably greater than or equal to 75%.

[0111] Generally, the bio-based carbon content of the raspberry ketone of the present invention is less than or equal to 110%, preferably less than or equal to 105%, more preferably less than or equal to 103%, more preferably less than or equal to 100%, and very preferably less than strictly 100%.

[0112] In the context of this invention, all carbon atoms of the raspberry ketone according to the invention are of bio-based origin; in particular, 10 carbon atoms of the raspberry ketone according to the invention are of bio-based origin. Preferably, 9 carbon atoms of the raspberry ketone are of bio-based origin; preferably, 8 carbon atoms, more preferably 7 carbon atoms, and more preferably 6 carbon atoms are of bio-based origin.

[0113] In all aspects of the invention, raspberry ketone may have a ratio (D / H)3 / (D / H)2 of less than or equal to 1.10, preferably less than or equal to 1.00, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.80.

[0114] In all aspects of the invention, raspberry ketone may have a ratio (D / H)3 / (D / H)2 greater than or equal to 0.10, preferably greater than or equal to 0.20, very preferably greater than or equal to 0.30 and very preferably greater than or equal to 0.40.

[0115] In all aspects of the invention, raspberry ketone may have a ratio (D / H)5 / (D / H)4 of less than or equal to 1.10, preferably less than or equal to 1.0, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.85.

[0116] In all aspects of the invention, raspberry ketone may have a ratio (D / H)5 / (D / H)4 greater than or equal to 0.10, preferably greater than or equal to 0.20, very preferably greater than or equal to 0.30 and very preferably greater than or equal to 0.40.

[0117] In the context of this invention, the raspberry ketone of this invention has a (D / H)3 / (D / H)2 ratio of less than or equal to 1.10, preferably less than or equal to 1.00, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.80, and a (D / H)5 / (D / H)4 ratio of less than or equal to 1.10, preferably less than or equal to 1.0, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.85. Generally, the raspberry ketone has a (D / H)3 / (D / H)2 ratio of greater than or equal to 0.10, preferably greater than or equal to 0.20, very preferably greater than or equal to 0.30, and very preferably greater than or equal to 0.40, and a (D / H)5 / (D / H)4 ratio of greater than or equal to 0.10, preferably greater than or equal to 0.20, very preferably greater than or equal to 0.30, and very preferably greater than or equal to 0.40.

[0118] As is well known to those skilled in the art, the sensory properties of flavoring substances can depend on the presence and amount of certain impurities. This is why the manufacturing method is crucial to the flavor of the final compound. Advantageously, the raspberry ketone of the present invention has been found to have satisfactory sensory properties. Notably, the sensory profile of the raspberry ketone of the present invention is equivalent to that of raspberry ketones extracted from fruits.

[0119] According to another aspect, the present invention covers the use of raspberry ketone according to the invention or raspberry ketone obtained by the method according to the invention as a flavoring agent or spice.

[0120] Finally, the present invention also covers compositions comprising raspberry ketone according to the invention, wherein the raspberry ketone is preferably selected from the group consisting of food, beverage, cosmetic formulation, pharmaceutical formulation and flavoring.

[0121] Example Example 1 Phenol was condensed with a 50% by weight solution of glyoxylic acid at 30°C in the presence of NaOH. The compound of formula (I) was obtained in 60% yield.

[0122] Example 2 After removing residual phenol, the compound of formula (I) obtained in Example 1 was oxidized in the presence of a metal catalyst (8% by weight) and heated to 75°C while being bubbled in an aqueous alkaline medium under autogenous pressure (6-8 bar). Acidification with H₂SO₄ yielded the compound of formula (IV) in 95% yield.

[0123] Example 3a The compound of formula (IV) obtained in Example 2 was condensed with acetone (4 equivalents) in acetic acid in the presence of sulfuric acid (0.5 equivalents) at 50°C. The compound of formula (VII) was obtained with 87% selectivity.

[0124] Example 3b The compound of formula (IV) obtained in Example 2 was condensed with acetone (8.6 equivalents) at 20°C in the presence of a 10% aqueous sodium hydroxide solution (2.2 equivalents). The compound of formula (VII) was obtained with 94% selectivity.

[0125] Example 3c The compound of formula (IV) obtained in Example 2 was condensed with acetone (4 equivalents) in DMSO at 58 °C in the presence of glycine (0.3 equivalents) and NaHCO3 (0.1 equivalents). The compound of formula (VII) was obtained with 83% selectivity.

[0126] Example 4a The compound of formula (VII) obtained in Example 3 was reduced in a solvent consisting of water and ethanol (1:1 mixture) in the presence of NaH2PO2·H2O (4 equivalents) and Pd / C (20 wt%). Raspberry ketone of formula (VII) was obtained with 81% selectivity.

[0127] Example 4b The compound of formula (VII) obtained in Example 3 was reduced in a solvent consisting of water and ethanol (1:1 mixture) in the presence of Na2HPO3·5H2O (4 equivalents) and Pd / C (20 wt%). Raspberry ketone of formula (VII) was obtained with 91% selectivity.

[0128] Example 4c The compound of formula (VII) obtained in Example 3 was reduced in a solvent consisting of water and ethanol (1:1 mixture) in the presence of HCO2H (4 equivalents) and Pd / C (20 wt%). Raspberry ketone of formula (VII) was obtained with 78% selectivity.

[0129] The raspberry ketone obtained by formula (VII) has 10 bio-based carbon atoms and isotopic deviations between -22‰ and -18‰.

[0130] The sensory characteristics of the raspberry ketone of the present invention are equivalent to those of the raspberry ketone extracted from fruit.

[0131] The embodiments of the present invention also include: Scheme 1. A method for preparing raspberry ketone, comprising step (a) of condensing phenol and glyoxylic acid according to the following scheme to form a compound of formula (I): .

[0132] Option 2. The method for preparing raspberry ketone as described in Option 1, comprising step (b) oxidizing the compound (I) obtained at the end of step (a) to form compound (IV).

[0133] Option 3. A method for preparing raspberry ketone as described in Option 2, comprising step (c) condensing the compound of formula (IV) obtained at the end of step (b) with acetone to form the compound of formula (VII).

[0134] Option 4. The method for preparing raspberry ketone as described in Option 3, comprising step (d) of hydrogenating the compound of formula (VII) obtained at the end of step (c).

[0135] Scheme 5. A method for preparing raspberry ketone as described in any one of Schemes 1 to 4, wherein at least one compound selected from phenol and glyoxylic acid is of bio-based origin, and optionally acetone.

[0136] Scheme 6. A method for preparing raspberry ketone, comprising the step of condensing 4-hydroxybenzyl alcohol with acetone.

[0137] Scheme 7. A raspberry ketone, characterized in that, on average... 13 The carbon isotope deviation is between -27‰ and -15‰.

[0138] Option 8. Raspberry ketone as described in Option 7, characterized in that the bio-based carbon content is greater than or equal to 50%.

[0139] Scheme 9. Raspberry ketone as described in any one of Schemes 7 and 8, characterized in that the bio-based carbon content is less than or equal to 110%.

[0140] Scheme 10. Raspberry ketone as described in any one of Schemes 7 to 9, characterized in that the ratio (D / H)5 / (D / H)4 is less than or equal to 1.10, preferably less than or equal to 1.0, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.85.

[0141] Scheme 11. Raspberry ketone as described in any one of Schemes 7 to 10, characterized in that the ratio (D / H)3 / (D / H)2 is less than or equal to 1.10, preferably less than or equal to 1.00, very preferably less than or equal to 0.90, and very preferably less than or equal to 0.80.

[0142] Scheme 12. Raspberry ketone as described in any one of Schemes 7 to 11, characterized in that the 10 carbon atoms are of bio-based origin.

[0143] Scheme 13. Use of raspberry ketone as described in any one of Schemes 7 to 12 or as obtained in the method described in Schemes 1 to 6 as a flavoring agent or spice.

[0144] Scheme 14. A composition comprising raspberry ketone as described in any one of Schemes 7 to 12 or raspberry ketone obtained as described in the methods of Schemes 1 to 6, wherein the raspberry ketone is preferably selected from the group consisting of food, beverage, cosmetic preparation, pharmaceutical preparation and flavoring.

Claims

1. A raspberry ketone, characterized in that, average 13 The carbon isotope deviation is between -27‰ and -15‰.

2. The raspberry ketone according to claim 1, characterized in that, The bio-based carbon content is greater than or equal to 50%.

3. The raspberry ketone according to any one of claims 1 and 2, characterized in that, The bio-based carbon content is less than or equal to 110%.

4. Raspberry ketone as described in any one of claims 1 and 2, characterized in that, The ratio (D / H)5 / (D / H)4 is less than or equal to 1.

10.

5. The raspberry ketone as described in claim 4, characterized in that, The ratio (D / H)5 / (D / H)4 is less than or equal to 1.

0.

6. The raspberry ketone according to claim 4, characterized in that, The ratio (D / H)5 / (D / H)4 is less than or equal to 0.

90.

7. The raspberry ketone according to claim 4, characterized in that, The ratio (D / H)5 / (D / H)4 is less than or equal to 0.

85.

8. Raspberry ketone as claimed in any one of claims 1 and 2, characterized in that, The ratio (D / H)3 / (D / H)2 is less than or equal to 1.

10.

9. The raspberry ketone as described in claim 8, characterized in that, The ratio (D / H)3 / (D / H)2 is less than or equal to 1.

00.

10. The raspberry ketone as described in claim 8, characterized in that, The ratio (D / H)3 / (D / H)2 is less than or equal to 0.

90.

11. The raspberry ketone as described in claim 8, characterized in that, The ratio (D / H)3 / (D / H)2 is less than or equal to 0.

80.

12. The raspberry ketone according to any one of claims 1 and 2, characterized in that, Ten carbon atoms are of bio-based origin.

13. Use of raspberry ketone as a flavoring agent or spice as claimed in any one of claims 1 to 12.

14. A composition comprising raspberry ketone as claimed in any one of claims 1 to 12.

15. The composition of claim 14, wherein the composition is selected from the group consisting of food, beverage, cosmetic preparation, pharmaceutical preparation and flavoring.

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