METHOD FOR THE PREPARATION OF POLYOL-BASED ESTERS OF KETOCARBON ACIDS

Description

[0001] The present invention relates to the field of ketone bodies and the associated metabolism, as well as the therapy of related diseases.

[0002] In particular, the present invention relates to a process for the production of polyglycerol esters of 3-oxobutyric acid (also referred to as "3-oxobutanoic acid", "beta-oxobutyric acid", "beta-oxobutanoic acid", etc.) and the reaction products obtainable or produced in this way (i.e., polyglycerol esters of 3-oxobutyric acid) and their functionalized derivatives.

[0003] Furthermore, the present invention relates to pharmaceutical compositions, in particular pharmaceuticals or medicines, comprising the reaction products obtainable or produced according to the manufacturing process according to the invention (i.e. polyglycerol esters of 3-oxobutyric acid) or their functionalized derivatives, as well as their applications or uses.

[0004] Finally, the present invention relates to food and / or food products, in particular food supplements and functional foods. (Functional Food), Novel Food, Food additives, nutritional supplements, dietary foods, power snacks, appetite suppressants and strength and / or endurance sports supplements, which include the reaction products obtainable or produced according to the manufacturing process according to the invention (i.e. polyglycerol esters of 3-oxobutyric acid) or their functionalized derivatives, as well as their applications or uses.

[0005] In human energy metabolism, glucose is the readily available energy carrier, which is metabolized into energy in the mitochondria, releasing water and carbon dioxide. However, the liver's glycogen stores are depleted during sleep. Yet, the human central nervous system (CNS) and the heart, in particular, require a constant energy supply.

[0006] The physiological alternative to glucose, which is primarily available to the central nervous system, are the so-called ketone bodies (also known as "ketone bodies" or, in English, as ketones). "Keton Bodies" designated).

[0007] The term "ketone bodies" is a collective term for three compounds that are primarily formed in catabolic metabolic states (such as during starvation, weight-loss diets, or low-carbohydrate diets) and can potentially lead to ketosis. The term "ketone bodies" specifically encompasses the three compounds acetoacetate (also known as acetoacetate or 3-oxobutyrate), acetone, and 3-hydroxybutyric acid (hereinafter also referred to as beta-hydroxybutyric acid or BHB or 3-BHB) or its salt (i.e., 3-hydroxybutyrate or beta-hydroxybutyrate).

[0008] These ketone bodies are also physiologically produced in large numbers during fasting or starvation from lipids stored in the body through lipolysis and almost completely replace the energy carrier glucose.

[0009] Ketone bodies are produced in the liver from acetyl-coenzyme A (acetyl-CoA), which originates from beta-oxidation; they represent a transportable form of acetyl-coenzyme A in the human body. To utilize ketone bodies, however, the brain and muscles must first adapt by expressing enzymes required to convert ketone bodies back into acetyl-coenzyme A. Particularly during periods of fasting, ketone bodies contribute significantly to energy production. For example, after some time, the brain can function with only one-third of its daily glucose requirement.

[0010] Physiologically, ketone bodies are synthesized from two molecules of activated acetic acid in the form of acetyl-coenzyme A, the normal intermediate of fatty acid degradation. First, acetoacetyl-coenzyme A is formed with the help of acetyl-coenzyme A acetyltransferase. This is then elongated to the intermediate 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) using another acetyl-coenzyme A unit and the enzyme HMG-CoA synthase. Finally, HMG-CoA lyase cleaves off the acetoacetate. These three steps take place exclusively in the mitochondria of the liver (Lynen cycle). In the cytosol, acetoacetate is ultimately converted to 3-hydroxybutyrate by the enzyme D-beta-hydroxybutyrate dehydrogenase. HMG-CoA is also an end product of the breakdown of the amino acid leucine, while acetoacetate is produced during the breakdown of the amino acids phenylalanine and tyrosine.

[0011] Acetoacetate is thus reductively converted under physiological conditions into the physiologically relevant form of 3-hydroxybutyric acid or 3-hydroxybutyrate.

[0012] 3-Hydroxybutyric acid itself is currently used and marketed in the field of strength sports as a sodium, magnesium or calcium salt.

[0013] However, 3-hydroxybutyric acid is either not known to humans from an evolutionary perspective or only exists in very small quantities, as plants do not produce it and it is only found in dead, emaciated animals in ketosis. Therefore, oral administration of 3-hydroxybutyric acid induces nausea. Furthermore, 3-hydroxybutyric acid, in its free form and its salts, has a very bitter taste and can cause severe vomiting and nausea.

[0014] Furthermore, patients, especially newborns but also adults, cannot permanently tolerate larger amounts of 3-hydroxybutyric acid salts, as these compounds can damage the kidneys.

[0015] Furthermore, the plasma half-life of 3-hydroxybutyric acid and its salts is so short that even with an intake of several grams, ketosis only lasts for approximately three to four hours. This means that patients, especially during the night, cannot continuously benefit from therapy with 3-hydroxybutyric acid or its salts. In patients with metabolic disorders, this can lead to life-threatening situations.

[0016] Therefore, in the case of the therapy of such metabolic diseases, so-called medium-chain triglycerides, so-called MCTs, are used today for ketogenic therapy, i.e. the metabolic conversion of caproic, caprylic and capric acid (i.e. of saturated linear C 6, C 8 and C 10 fatty acids) from the corresponding triglycerides is intended.

[0017] In principle, from a pharmaceutical and clinical point of view, acetoacetate, as the physiological precursor of 3-hydroxybutyric acid, represents a more effective pharmaceutical-pharmacological target molecule, which, according to the state of the art, could in principle be used for the therapy of a large number of diseases (e.g., diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, or neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, etc., lipid metabolism disorders, etc.), but cannot be used there due to its lack of physiological compatibility or availability.

[0018] The following table illustrates, purely by way of example but by no means as a limitation, potential therapeutic options or possible indications for the active ingredient acetoacetate or the physiologically obtainable 3-hydroxybutyric acid or its salt (i.e. 3-hydroxybutyrate) by reduction of acetoacetate. indication Therapeutic effect Traumatic brain injury Reduction of apoptosis and necrosis rates in nerve cells stroke Reduction of apoptosis and necrosis rates in nerve cells Refeeding syndrome In cases of anorexia, discontinuation of enteral or parenteral nutrition, and after prolonged periods of starvation, the consumption of starch or glucose can lead to death (see also the WHO Peanut Butter Scheme). Acetoacetate, or the physiologically generated BHB derived from it, can be used therapeutically in these situations to accelerate the restoration of normal food intake. Appetite suppressant Suppression of the feeling of hunger in the central nervous system (CNS) epilepsy Conventional ketogenic diets for significantly reducing seizure frequency are extremely poorly tolerated by patients. Acetoacetate, or the physiologically generated BHB derived from it, offers a readily effective alternative. Alzheimer's disease, dementia Improving the cognitive performance of patients: Acetoacetate or physiologically generated BHB is also effective for the prevention of neurodegenerative diseases. Disorders of fatty acid oxidation (e.g., electron transfer protein defect) Compensation for a nutrient deficiency in case of a defect in energy metabolism.

[0019] Therefore, from a pharmaceutical and clinical point of view, it is desirable to be able to find effective precursors or metabolites which physiologically allow direct or indirect access to acetoacetate (and thus also physiological access to 3-hydroxybutyric acid or its salts), especially in the physiological metabolism of the human or animal body.

[0020] Consequently, there has been no shortage of attempts in the prior art to find physiologically suitable precursors or metabolites for 3-hydroxybutyric acid or its salts. However, no efficient compounds of this kind have yet been found in the prior art. Furthermore, access to such compounds is not currently possible or readily available according to the prior art.

[0021] WO 2008 / 005818 A1 concerns alternative sources of ketone bodies for reducing or eliminating the symptoms of Parkinson's disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), Alzheimer's disease, Huntington's disease, epilepsy, and other diseases or disorders characterized by impaired glucose metabolism, wherein the alternative sources of ketone bodies include mono-, di-, or triglyceride esters of acetoacetate and mixtures thereof, or mono-, di-, or triglyceride esters of 3-hydroxybutyrate and mixtures thereof, wherein the glyceride esters can be administered orally as a food supplement or in a nutrient composition.

[0022] Furthermore, the scientific publication by Michael J. Haas et al., European Journal of Lipid Science and Technology, Vol. 113, No. 2, February 1, 2011, pages 168-179, concerns the use of immobilized Rhizomucor-miehei-Lipase in the synthesis of partial acylglycerols from acetoacetate, wherein from the esterification of glycerol with ethyl acetoacetate both 1(3)- sn- Monoacetoacetylglycerol (MAcG) as well as 1,3-sn-diacetoacetylglycerol (DAcG) result, with various reaction conditions for the complete conversion of the glycerol to a mixture of mono- and diacetoacetyles being analyzed.

[0023] Furthermore, the scientific publication by Sanjib Kumar Karmee et al., Synthetic Communications, Vol. 35, No. 9, May 1, 2005, pages 1151-1160, concerns the selective transesterification of polyols with keto esters by microwave irradiation under solvent-free and catalyst-free conditions to form the corresponding monoesters.

[0024] Furthermore, US 3,907,994 A relates to alkyl esters of quinoxaline di-N-oxide-2-carboxylic acid, which are substituted at the alkyl group of the ester by hydroxy, acyloxy, N-alkylcarbamyloxy, dialkylaminoacyloxy, carboxyacyloxy, alkoxycarbonyloxy, halogenacyloxy and amino as well as mono- and disubstituted amino groups, wherein these alkyl esters are intended to be used as antibacterial agents and to promote growth and improve feed efficiency in animals in general.

[0025] Publication GB 2 046 091 A concerns pharmaceutical compositions for oral or rectal administration which comprise (1) a specific β-diketone compound; and (2) a pharmacologically active substance (e.g. insulin, β-lactam antibiotics), wherein the β-diketones according to (1) are intended to promote the absorption of the pharmacologically active substance via the intestinal tract.

[0026] Furthermore, publication JP 2007 277441 A concerns the provision of a plasticizer for a biodegradable resin with low odor and flexibility, and the provision of a biodegradable resin composition with low odor and low flexibility, wherein the plasticizer comprises a compound with at least one acetoacetic acid ester group.

[0027] Furthermore, US 2009 / 253781 A1 concerns compositions comprising ketone bodies or their metabolic precursors, suitable for administration to humans or animals, which have, among other properties, (i) increased cardiac efficiency, particularly the efficiency of glucose utilization; (ii) provision of an energy source, particularly in cases of diabetes and insulin resistance; and (iii) treatment of disorders caused by damage to brain cells, particularly by delaying or preventing brain damage in memory-associated brain regions, such as that seen in Alzheimer's disease or similar disorders. US 2009 / 253781 A1 also covers the use of these compositions as nutritional aids, for example, for athletes, or for the treatment of conditions, particularly those associated with poor cardiac function, insulin resistance, and neuronal damage.

[0028] Furthermore, WO 95 / 09146 A1 concerns compositions intended to be useful as nutrients, wherein the compositions comprise sterile aqueous solutions containing an effective amount of at least one glycerol bisacetoacetate, and wherein the compositions are intended to be useful as a substitute for glucose in intravenous feeding.

[0029] Document WO 90 / 02549 A1 concerns a nutrient for humans or animals which contains at least one glyceride of at least one keto acid or hydroxy acid that is not readily soluble in water, wherein the nutrient can be administered with food or in the form of an emulsion of the glyceride.

[0030] Furthermore, US 2009 / 137710 A1 relates to an organosilicon compound with a β-ketoester structure and an adhesive composition for a liquid crystal element containing the organosilicon compound.

[0031] Furthermore, EP 0 022 978 A1 relates to unsaturated acetoacetic acid esters suitable as comonomers in the polymerization of unsaturated compounds in aqueous medium, wherein acetylacetoxyalkyl allyl ethers are particularly suitable, wherein the allyl ether derivatives are produced in particular by reacting an allyl alcohol with an epoxide and subsequently reacting the resulting hydroxyalkyl allyl ether with diketene, wherein both reaction steps are carried out at a temperature of 0 to 100 °C, preferably in the presence of a catalyst, and the obtainable allyl ether derivatives are said to be copolymerizable, for example, with vinyl compounds such as vinyl esters, acrylic esters, olefins, vinyl halides and vinyl aromatics.

[0032] Finally, US 2003 / 064954 A1 concerns amphiphilic 1,4-dihydropyridine derivatives intended for the manufacture of a composition for the delivery of nucleotide-containing compounds into a target cell or its nucleus, wherein the composition comprises 1,4-dihydropyridine derivatives with DNA condensation capacity and the ability to self-associate. Furthermore, US 2003 / 064954 A1 concerns compositions comprising the derivatives complexed with nucleotide-containing compounds, as well as methods for the manufacture of the complexes and the use of the 1,4-dihydropyridine derivatives for the manufacture of systems for the delivery of nucleotide-containing compounds, which are intended to be useful in gene therapy and DNA vaccination.

[0033] The problem underlying the present invention is therefore to provide an efficient manufacturing process for physiologically suitable or physiologically compatible precursors and / or metabolites of acetoacetate or ultimately of 3-hydroxybutyric acid (i.e., beta-hydroxybutyric acid or BHB or 3-BHB) or their salts.

[0034] Such a process should in particular make acetoacetate or the relevant BHB precursors and / or BHB metabolites accessible in an efficient manner, especially in larger quantities and without significant amounts of toxic by-products.

[0035] In a completely unexpected manner, the applicant has now discovered that polyglycerol esters of 3-oxobutyric acid represent an efficient and physiologically active or physiologically compatible precursor and / or metabolite for the ketone body acetoacetate or for the 3-hydroxybutyric acid or its salts reductively produced from it under physiological conditions, and has been able to find or develop an efficient manufacturing process for these compounds, which enables direct and effective, in particular economical as well as industrially feasible access to these compounds.

[0036] To solve the problem described above, the present invention therefore proposes – according to a first Aspect of the present invention - a process for the preparation of polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid) according to claim 1; further, in particular special and / or advantageous embodiments of this process according to the invention are the subject of the corresponding dependent process claims.

[0037] Furthermore, the present invention relates – according to a second Aspect of the present invention - a process for the preparation of functionalized, in particular fatty acid functionalized, polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid) according to claim 6.

[0038] Furthermore, the present invention relates – according to a third Aspect of the present invention - an optionally functionalized polyglycerol ester of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid) or mixtures thereof according to the relevant claims (claims 7 to 13); further, in particular special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claims.

[0039] Likewise, the present invention relates – according to a fourth Aspect of the present invention - a pharmaceutical composition, in particular a drug or medicine, according to the relevant independent claim (claim 15); further, in particular special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claim.

[0040] Furthermore, the present invention relates – according to a fifthAspect of the present invention - a food and / or food product according to the related independent claim (claim 17).

[0041] It goes without saying that the following explanations state that embodiments, designs, advantages and the like, which are described below for the purpose of avoiding repetition only with regard to one aspect of the invention, naturally also apply to the other aspects of the invention without the need for separate mention.

[0042] Furthermore, it goes without saying that individual aspects and embodiments of the present invention shall also be deemed disclosed in any combination with other aspects and embodiments of the present invention, and in particular any combination of features and embodiments as they result from the cross-references of all claims shall be deemed to be extensively disclosed, with regard to all possible combinations.

[0043] With regard to all the relative or percentage weight-related specifications mentioned below, in particular relative quantity or weight specifications, it should also be noted that, within the scope of the present invention, these must be selected by the person skilled in the art in such a way that, in sum, including all components or ingredients, in particular as defined below, they always add up to 100% or 100% by weight; however, this is self-evident to the person skilled in the art.

[0044] Furthermore, it should be noted that the person skilled in the art may, if necessary, deviate from the scope specifications listed below, either in relation to the application or due to the specific circumstances of the case, without leaving the scope of the present invention.

[0045] Furthermore, it should be noted that all values ​​or parameters mentioned below, or the like, can generally be determined using standardized or explicitly specified determination procedures, or alternatively, using determination or measurement methods that are generally familiar to those skilled in the art in this field.

[0046] Having said that, the present invention will now be explained in detail below.

[0047] Subject matter of the present invention - according to a first An aspect of the present invention is thus a process for the preparation of polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), wherein at least one compound of the general formula (I) CH 3 - C(O) - CH 2 - C(O)OR 1< (I) wherein in general formula (I) the residue R 1< represents a C 1 -C 4 alkyl, in particular methyl or ethyl, preferably ethyl, is reacted with at least one polyglycerol of general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in general formula (IIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, wherein the reaction is carried out in the absence of solvents and wherein the reaction is carried out in the presence of a catalyst, such that one or more 3-oxobuteric acid polyglycerol esters are obtained as the reaction product, wherein the compound according to general formula (IV) R 1< - OH (IV) is formed simultaneously during the reaction, wherein in general formula (IV) the residue R 1< is a C 1 -C 4 alkyl, in particular methyl or ethyl, preferably Ethyl, represents,where the compound is continuously withdrawn according to the general formula (IV) of the reaction.

[0048] As previously stated, the applicant has discovered, quite unexpectedly, that the polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid) produced in this way – also referred to as "3-oxobutyric acid polyglycerol esters" – represent efficient, because physiologically compatible, precursors and / or metabolites of 3-hydroxybutyric acid or its salts, which can be used pharmaceutically or clinically in larger quantities because they are physiologically compatible.

[0049] The aforementioned polyglycerol esters of 3-oxobutyric acid, which are made available for the first time in an efficient manner by the manufacturing process according to the invention, represent a physiologically and pharmacologically relevant alternative to free 3-hydroxybutyric acid or its salts.

[0050] The production of polyglycerol esters of 3-oxobutyric acid via conventional organic synthesis is complex and costly because 3-oxobutyric acid is unstable and decomposes. Within the scope of the present invention, an efficient production process has been provided for the first time, enabling the synthesis of polyglycerol esters of 3-oxobutyric acid without undesirable side reactions, particularly in a single step.

[0051] The process according to the invention thus enables, for the first time, the provision of non-toxic polyglycerol esters of 3-oxobutyric acid from known, commercially available, and, above all, physiologically harmless components or starting materials. The resulting polyglycerol esters of 3-oxobutyric acid can be physiologically broken down, particularly in the stomach and / or intestine, releasing or generating the target molecule "acetoacetate (acetate acetate)" and ultimately "3-hydroxybutyric acid" or its salts as the active ingredient or active component.

[0052] Furthermore, the aforementioned polyglycerol esters of 3-oxobutyric acid also have an acceptable taste to ensure compatibility even when larger quantities are administered orally over a longer period (e.g., administration of 50 g daily dose or more).

[0053] Likewise, the manufacturing process according to the invention makes it possible to provide the polyglycerol esters of 3-oxobutyric acid free from toxic impurities.

[0054] Furthermore, the manufacturing process according to the invention, including optional further processing or purification process steps, is economically viable and can also be implemented on an industrial scale.

[0055] In particular, the manufacturing process according to the invention uses commercially available starting materials, which enable an economically efficient and, moreover, a relatively simple process control, even in large-scale industrial implementation.

[0056] In contrast to conventional manufacturing processes of the prior art, the manufacturing process according to the invention requires no complex starting materials and proceeds in a single step. Nevertheless, excellent yields are achieved using the manufacturing process according to the invention, while the formation of by-products is minimized or avoided. In particular, the dimerization of a 3-hydroxybutyric acid precursor or metabolite can be prevented by the starting materials used according to the invention.

[0057] Furthermore, the process according to the invention is simple and economical. The process according to the invention is carried out in the absence of solvents and / or without any solvent at all (i.e., as a mass reaction or as a substance reaction or as a so-called Bulk ReactionConsequently, the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Furthermore, no toxic byproducts are formed.

[0058] The manufacturing process according to the invention typically leads to a mixture of different polyglycerol esters of 3-oxobutyric acid, i.e., a mixture of at least two, and in particular at least three, different polyglycerol esters of 3-oxobutyric acid. The resulting crude reaction product or crude mixture can be purified by methods known per se, in particular by removing any remaining reactants and / or byproducts, and furthermore—if desired—by further cleavage using methods also known per se, in particular by distillation and / or chromatography (e.g., fractionation into the individual polyol esters, i.e., mono-, di-, tri-, etc. polyol esters of 3-oxobutyric acid, or fractionation into fractions with enriched and depleted proportions of individual fractions, etc.).

[0059] Furthermore, the manufacturing process according to the invention does not require enantioselective reaction control, since the formation or release of the active ingredient 3-hydroxybutyric acid in the gastrointestinal tract generally occurs in the physiologically relevant form of the R-enantiomer.

[0060] According to the invention, it is preferred if in the general formula (I) the residue R 1< represents ethyl.

[0061] In other words, according to the invention it is preferred that 3-oxybutyric acid ethyl ester (ethyl 3-oxobutyrate) of the formula CH 3 - C(O) - CH 2 - C(O)OC 2 H 5 is used as the compound of the general formula (I).

[0062] This enables particularly efficient process control and high yields with minimized or suppressed byproduct formation. Furthermore, ethyl 3-oxobutyric acid is commercially available in large quantities and, unlike the free acid (i.e., 3-oxobutyric acid), is stable and therefore easier to use. In particular, ethyl 3-oxobutyric acid can be produced industrially as a starting compound, for example, by Claisen condensation of ethyl acetate.

[0063] In the process according to the invention, the reaction is carried out in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk ReactionThis has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0064] According to the present invention, the reaction is carried out in the presence of a catalyst, in particular an enzyme and / or a metal-containing and / or metal-based acidic or basic catalyst. In this particular embodiment, it is preferred if the catalyst is recycled after the reaction.

[0065] As previously stated, according to a particular embodiment of the manufacturing process according to the invention, the reaction can be carried out in the presence of an enzyme as a catalyst.

[0066] The enzyme can be selected, in particular, from synthetases (ligases), catalases, esterases, lipases, and combinations thereof. According to the invention, synthetases (synonymous with ligases) are specifically enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by a covalent bond. Catalases, as used in the present invention, are in particular enzymes capable of converting hydrogen peroxide to oxygen and water. The term esterases refers in particular to enzymes capable of hydrolytically cleaving esters into alcohols and acids (saponification); these are therefore, in particular, hydrolases, with fat-splitting esterases also being referred to as lipases. Lipases, as used in the present invention, are in particular enzymes capable of cleaving free fatty acids from lipids, such as glycerides (lipolysis).

[0067] Within the scope of the present invention, the enzyme used as a catalyst can in particular be derived from Candida antarctica, Mucor miehei (Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar and Pseudomonas sp. and their combinations, preferably of Candida antarctica, Mucor miehei (Rhizomucor miehei) and Thermomyces lanuginosus.

[0068] According to a particular embodiment, the enzyme can be used in immobilized form, immobilized on a support, preferably on a polymeric support, preferably on a polymeric organic support, particularly preferably with hydrophobic properties, most preferably on a poly(meth)acrylic resin-based support.

[0069] As previously explained in connection with the use of a catalyst in general, it is preferable, in the case of using an enzyme as a catalyst, to recycle the enzyme after the reaction.

[0070] If the reaction is carried out in the presence of an enzyme as a catalyst within the framework of the manufacturing process according to the invention, it is preferred if the reaction is carried out at temperatures in the range of 10 °C to 80 °C, in particular in the range of 20 °C to 80 °C, preferably in the range of 25 °C to 75 °C, particularly preferably in the range of 45 °C to 75 °C, and most preferably in the range of 50 °C to 70 °C.

[0071] When an enzyme is used as a catalyst, the amount of enzyme employed can vary widely. In particular, the enzyme can be used in amounts, relative to the total amount of starting compounds (I) and (IIb), ranging from 0.001 wt% to 20 wt%, more specifically from 0.01 wt% to 15 wt%, preferably from 0.1 wt% to 15 wt%, and more preferably from 0.5 wt% to 10 wt%. However, depending on the specific case or application, it may be necessary to deviate from the aforementioned amounts without departing from the scope of the present invention.

[0072] If, according to a particular embodiment of the present invention, the reaction is carried out in the presence of an enzyme as a catalyst, the applied pressure range can also vary widely. In particular, when carried out in the presence of an enzyme as a catalyst, the reaction can be carried out at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, most preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0073] According to an alternative embodiment of the present invention, the reaction can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst.

[0074] According to this alternative embodiment of the present invention, wherein the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the catalyst may in particular be selected from (i) basic catalysts, in particular alkali or alkaline earth hydroxides and alkali or alkaline earth alcoholates, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe and Na(OBu-tert.), (ii) acidic catalysts, in particular mineral acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminium compounds, such as titanium tetrabutylate, stannic acids, zinc acetate, aluminium trichloride and aluminium triisopropyl and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminium oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas, and combinations thereof.

[0075] In this embodiment, an alkali or alkaline earth alcoholate can be used as a catalyst.

[0076] In particular, it is also preferred in this embodiment if the catalyst based on the metal-containing and / or metal-based acidic or basic catalyst is recycled after the reaction.

[0077] If, according to a particular embodiment of the present invention, the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the temperatures can be varied over a wide range. In particular, the reaction in the presence of a metal-containing and / or metal-based acidic or basic catalyst can be carried out at temperatures in the range of 20 °C to 150 °C, particularly in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0078] Furthermore, in this embodiment, the catalyst (i.e., the metal-containing and / or metal-based, acidic or basic catalyst) can also be varied over a wide range of quantities: The catalyst based on a metal-containing and / or metal-based, acidic or basic catalyst can be used in amounts, relative to the total amount of starting compounds (I) and (IIb), in the range of 0.01 wt.% to 30 wt.%, particularly in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, and more preferably in the range of 0.2 wt.% to 10 wt.%. However, depending on the application or specific circumstances, it is possible to deviate from the aforementioned quantities without departing from the scope of the present invention.

[0079] If, according to this particular embodiment of the present invention, the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the pressure range can likewise vary over a wide range: In particular, the reaction can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0080] As for the quantity of reactants or starting compounds, this can also be varied widely.

[0081] Taking into account process economy and optimization of the process flow, especially with regard to minimizing by-products, it is advantageous if the compound of general formula (I), based on the hydroxyl groups of the polyglycerol (IIb), is used in molar amounts in a range from equimolar amount up to a molar excess of 200 mol%, in particular in a range from equimolar amount up to a molar excess of 150 mol%, preferably in a range from equimolar amount up to a molar excess of 100 mol%.

[0082] Equally taking into account process economy and optimization of the process flow, especially with regard to minimizing by-products, it is advantageous if the compound of general formula (I) and the polyglycerol (IIb) are used in a molar ratio of compound of general formula (I) / polyglycerol (IIb) in a range of 1 :1 to 10 : 1, in particular in a range of 2 : 1 to 8 : 1, preferably in a range of 3 : 1 to 6 : 1.

[0083] According to the process according to the invention, the polyglycerol corresponds to the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in the general formula (IIb) the variable p is an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1.

[0084] According to a further particular embodiment of the process according to the invention, the polyglycerol (IIb) can be a diglycerol of formula (IIc) HO - CH 2 - CH(OH) - CH 2 - O - CH 2 - CH(OH) - CH 2 - OH (IIc).

[0085] According to a preferred embodiment of the process according to the invention, the polyglycerol (IIb) is not propane-1,2,3-triol, i.e., the polyglycerol (IIb) is not glycerol.

[0086] According to a preferred embodiment of the present invention, the present invention relates, according to this aspect of the invention, to a process for the preparation of polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), in particular a process as described above, wherein at least one compound of the general formula (I) CH 3 - C(O) - CH 2 - C(O)OR 1< (I) wherein in the general formula (I) the residue R 1< represents a C 1 -C 4 alkyl, in particular methyl or ethyl, preferably ethyl, with at least one polyglycerols of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in the general formula (IIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, is reacted such that one or more 3-oxobuteric acid polyglycerol esters are obtained as the reaction product.

[0087] According to a further preferred embodiment of the present invention, the present invention relates, according to this aspect of the invention, to a process for the production of polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), in particular a process as described above, wherein at least one compound of the general formula (I) CH 3 - CH(OH) - CH 2 - C(O)OR 1< (I) where in the general formula (I) the residue R 1< represents ethyl, is reacted with at least one polyglycerols of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) where in the general formula (IIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, such that one or more 3-oxobuteric acid polyglycerol esters are obtained as the reaction product.

[0088] A particularly preferred method according to the invention is illustrated by the following reaction or synthesis scheme (where, depending on the reaction procedure, either individual esters or a mixture of two or more thereof are obtained):

[0089] In the process according to the invention, the compound according to the general formula (IV) R 1< - OH (IV) is formed simultaneously during the reaction, wherein in the general formula (IV) the residue R 1< represents a C 1 -C 4 -alkyl, in particular methyl or ethyl, preferably ethyl.

[0090] In this context, it is intended that the compound according to the general formula (IV) is continuously removed from the reaction, in particular preferably by continuous distillation. In this way, the reaction equilibrium is efficiently shifted towards the side of the reaction products. The formation of by-products is also minimized or prevented in this way.

[0091] Within the framework of the manufacturing process according to the invention, the reaction product, in particular the composition of the reaction product, especially the presence of various 3-oxobutyric acid polyglycerol esters and their proportion in the case of a mixture, can be controlled and / or controlled by means of the reaction conditions, in particular by selecting the reaction temperature and / or selecting the reaction pressure and / or providing a catalyst and its selection with regard to type and / or quantity and / or selecting the quantities of the starting compounds and / or providing the removal of the compound according to the general formula (IV), as defined above.

[0092] Following the reaction, the resulting product can be subjected to further usual or known purification or work-up steps.

[0093] In this context, the reaction product obtained after the reaction has taken place can be fractionated, in particular fractionated by distillation.

[0094] Unreacted starting compounds (I) and / or (IIb) can also be separated from the reaction product and subsequently recycled.

[0095] According to a particular embodiment of the manufacturing process according to the invention, it is particularly possible to proceed such that any hydroxyl groups still present in the reaction product after the reaction have taken place are at least partially, preferably completely, functionalized, in particular by esterification. In particular, the reaction can be followed by a partial, in particular complete, functionalization, in particular esterification, of any remaining hydroxyl groups.

[0096] In this particular embodiment of the process according to the invention, the functionalization, in particular esterification, of the hydroxyl groups in the reaction product can be carried out with at least one carboxylic acid anhydride of the general formula (V) R 3< - O - R 3< (V) wherein in the general formula (V) the residue R 3< is, independently of each other, the same or different, a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -; and / or wherein in the general formula (V) the residue R 3< is, independently of each other, the same or different, a fatty acid residue, in particular a C 5 -C 34 -fatty acid residue, preferably a C 8 -C 34 -fatty acid residue.

[0097] Furthermore, in this particular embodiment of the process according to the invention, it is preferred if the carboxylic acid anhydride of the general formula (V) is a fatty acid anhydride, preferably a C 5 -C 34 fatty acid anhydride, preferably a C 8 -C 34 fatty acid anhydride.

[0098] In particular, it is preferred if the carboxylic anhydride of general formula (V) is a compound in which the R 3< substituents are identical. In other words, a symmetrical carboxylic anhydride of general formula (V) is used.

[0099] According to an alternative embodiment, it is preferred if the carboxylic anhydride of general formula (V) is a compound in which the R 3< substituents are different from each other. In other words, an unsymmetrical carboxylic anhydride of general formula (V) is used.

[0100] According to the invention, the functionalization of the hydroxyl groups still present in the reaction product after the reaction has taken place with the at least one carboxylic acid anhydride of the general formula (V) can be carried out at temperatures in the range of 60 to 150 °C, in particular in the range of 70 to 120 °C, preferably in the range of 80 to 100 °C.

[0101] The functionalization according to the invention of the hydroxyl groups still present in the reaction product after conversion with the at least one carboxylic acid anhydride of general formula (V) can be carried out in particular at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0102] In particular, it is preferred if the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with the at least one carboxylic anhydride of general formula (V) in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk Reaction This has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0103] Within the framework of the functionalization according to the invention of the hydroxyl groups still present in the reaction product according to the invention with the at least one carboxylic acid anhydride of the general formula (V) a compound according to the general formula (VI) R 3< - OH (VI) is formed simultaneously, wherein the residue R 3< has the meaning given above.

[0104] In this context, it is particularly preferred if the compound according to the general formula (VI) is removed during or after the reaction, especially after the reaction has taken place, preferably by distillation.

[0105] Following the functionalization according to the invention of the hydroxyl groups still present in the reaction product after the reaction with the at least one carboxylic acid anhydride of the general formula (V), the product obtained can be subjected to further conventional or known purification or work-up steps.

[0106] In this context, functionalization may be followed in particular by distillation and / or chromatography, preferably distillation.

[0107] In particular, any remaining reactants and reaction by-products, especially compounds according to the general formula (VI), are distilled off.

[0108] Within the framework of the functionalization according to the invention, in the case that the R 3< groups in the general formula (V) are different from one another, and / or in the case that the R 3< groups in the general formula (V) each represent an alkyl group with more than two carbon atoms, the carboxylic anhydride of the general formula (V) is obtained and / or the carboxylic anhydride of the general formula (V) is obtainable by reacting acetic anhydride with at least one carboxylic acid, in particular fatty acid, of the general formula (VI) R 3< - OH (VI) wherein the R 3< group has the meaning given above.

[0109] In this context, the reaction of acetic anhydride with at least one carboxylic acid, in particular fatty acid, of the general formula (VI) takes place in particular according to the reaction equation where the residue R 3< has the meaning given above, but with the proviso that the residues R 3< are different from each other and / or that the residues R 3< each independently represent an alkyl residue with more than two carbon atoms.

[0110] According to a particular embodiment of this process according to the invention, a symmetrical carboxylic anhydride of general formula (V) is produced. In other words, in general formula (V), the R 3< groups are identical and represent an alkyl group with more than two carbon atoms.

[0111] According to an alternative particular embodiment of this process according to the invention, an unsymmetrical carboxylic anhydride of general formula (V) is produced. Thus, in general formula (V), the R3< groups are different from one another; preferably, in general formula (V), the R3< groups each represent an alkyl group with more than two carbon atoms. According to an alternative embodiment of the functionalization, in particular esterification, of the hydroxyl groups remaining in the reaction product after the reaction has taken place, this can be carried out in particular by reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) R3< - O - R4< (VII), wherein in general formula (VII) the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -, and the residue R 4< is hydrogen or a C 1 -C 4 -alkyl, in particular methyl or ethyl, preferably hydrogen.

[0112] In this context, it is particularly preferred if the carboxylic acid and / or the carboxylic acid ester of general formula (VII) is a fatty acid and / or a fatty acid ester, preferably a C 5 -C 34 fatty acid and / or a C 5 -C 34 fatty acid ester, preferably a C 8 -C 34 fatty acid and / or a C 8 -C 34 fatty acid ester.

[0113] In particular, in this embodiment of the invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) in the absence of solvents and / or without any solvent at all. That is, the reaction is carried out as a mass reaction or as a substance reaction or as a so-called Bulk Reaction This has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0114] According to a preferred embodiment, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) in the presence of a catalyst, in particular an enzyme and / or a metal-containing and / or metal-based, acidic or basic catalyst.

[0115] In this context, it is particularly preferable if the catalyst is recycled after the conversion process.

[0116] As previously stated, according to a preferred embodiment, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction has taken place can be carried out with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (VII) in the presence of an enzyme as a catalyst.

[0117] The enzyme can be selected, in particular, from synthetases (ligases), catalases, esterases, lipases, and combinations thereof. According to the invention, synthetases (synonymous with ligases) are specifically enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by a covalent bond. Catalases, as used in the present invention, are in particular enzymes capable of converting hydrogen peroxide to oxygen and water. The term esterases refers in particular to enzymes capable of hydrolytically cleaving esters into alcohols and acids (saponification); these are therefore, in particular, hydrolases, with fat-splitting esterases also being referred to as lipases. Lipases, as used in the present invention, are in particular enzymes capable of cleaving free fatty acids from lipids, such as glycerides (lipolysis).

[0118] In this particular embodiment, the enzyme used as a catalyst can be derived from Candida antarctica, Mucor miehei (Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delemar and Pseudomonas sp. as well as combinations thereof, preferably from Candida antarctica, Mucor miehei (Rhizomucor miehei) and Thermomyces lanuginosus.

[0119] It is particularly preferred if the enzyme is used in immobilized form, in particular immobilized on a support, preferably on a polymeric support, preferably on a polymeric organic support, particularly preferably with hydrophobic properties, most preferably on a poly(meth)acrylic resin-based support.

[0120] As already explained in connection with the catalyst in general, it is preferable if the enzyme is recycled after the reaction.

[0121] If the functionalization according to the invention of the hydroxyl groups still present in the reaction product after the reaction has taken place with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (VII) is carried out in the presence of an enzyme as a catalyst, it is preferred if the reaction is carried out at temperatures in the range of 10 °C to 80 °C, in particular in the range of 20 °C to 80 °C, preferably in the range of 25 °C to 75 °C, particularly preferably in the range of 45 °C to 75 °C, most preferably in the range of 50 °C to 70 °C.

[0122] When using an enzyme as a catalyst, the amount of enzyme employed can vary widely. In particular, the enzyme can be used in amounts, relative to the total amount of the starting compounds, in the range of 0.001 wt% to 20 wt%, more specifically in the range of 0.01 wt% to 15 wt%, preferably in the range of 0.1 wt% to 15 wt%, and more preferably in the range of 0.5 wt% to 10 wt%. However, depending on the specific case or application, it may be necessary to deviate from the aforementioned amounts without departing from the scope of the present invention. In this context, the starting compounds are the 3-oxobutyric acid polyol esters (III) and the carboxylic acid and / or the carboxylic acid ester of the general formula (VII).

[0123] If, according to a particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction is carried out with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) in the presence of an enzyme as a catalyst, the pressure range used can also vary widely. In particular, when carried out in the presence of an enzyme as a catalyst, the reaction can be carried out at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, most preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0124] According to an alternative embodiment of the functionalization according to the invention of the hydroxyl groups still present in the reaction product after reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII), the functionalization can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst.

[0125] According to this alternative embodiment of the functionalization according to the invention, wherein the functionalization is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the catalyst may in particular be selected from (i) basic catalysts, in particular alkali or alkaline earth hydroxides and alkali or alkaline earth alcoholates, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe and Na(OBu-tert.), (ii) acidic catalysts, in particular mineral acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminium compounds, such as titanium tetrabutylate, stannic acids, zinc acetate, aluminium trichloride and aluminium triisopropyl and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminium oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas, and combinations thereof.

[0126] In this embodiment, an alkali or alkaline earth alcoholate can be used as a catalyst.

[0127] In particular, in this embodiment of the functionalization, it is also preferred if the catalyst based on the metal-containing and / or metal-based acidic or basic catalyst is recycled after the reaction.

[0128] If, according to this particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the temperatures can be varied over a wide range. In particular, the reaction in the presence of a metal-containing and / or metal-based acidic or basic catalyst can be carried out at temperatures in the range of 20 °C to 150 °C, particularly in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0129] Furthermore, in this embodiment, the catalyst (i.e., the metal-containing and / or metal-based, acidic or basic catalyst) can also be varied over a wide range of quantities: The catalyst, based on a metal-containing and / or metal-based, acidic or basic catalyst, can be used in amounts, relative to the total amount of the starting compounds, in the range of 0.01 wt.% to 30 wt.%, particularly in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, and more preferably in the range of 0.2 wt.% to 10 wt.%. However, depending on the application or specific circumstances, it is possible to deviate from the aforementioned amounts without departing from the scope of the present invention. In this context, the starting compounds are the 3-oxobutyric acid polyol esters (III) and the carboxylic acid and / or the carboxylic acid ester of the general formula (VII).

[0130] If, according to this particular embodiment of the present invention, the functionalization of the hydroxyl groups remaining in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of general formula (VII) is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, the pressure range can likewise vary over a wide range: In particular, the reaction can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0131] Within the framework of this particular embodiment of the functionalization of the hydroxyl groups still present in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (VII), a compound of the general formula (VIII) R 4< - OH (VIII) is formed simultaneously, wherein the residue R 4< has the meaning given above.

[0132] In this context, it is particularly preferred if the compound of general formula (VIII) is removed during or after the reaction, especially during the reaction, preferably by distillation. This efficiently shifts the reaction equilibrium towards the products. It also minimizes or prevents the formation of byproducts.

[0133] According to a particular embodiment of the process according to the invention, the ester groups introduced into the reaction product (III) by the previously described process can be subjected to partial transesterification using a compound of the general formula (VII), as defined above. In other words, the ester groups introduced into the reaction product (III) by the previously described process can be partially exchanged by a residue R 3< with the meaning given above by means of transesterification.

[0134] In this context, the transesterification according to this particular embodiment of the present invention can be carried out under reaction conditions as previously described for the inventive functionalization of the hydroxyl groups still present in the reaction product after the reaction with at least one carboxylic acid and / or a carboxylic acid ester.

[0135] A particularly preferred method according to the invention, which provides for the functionalization, in particular esterification, of any remaining hydroxyl groups following the reaction, is illustrated by the following reaction or synthesis scheme (where, depending on the reaction procedure, either single esters or a mixture of two or more thereof are obtained during the reaction, and where, in the following reaction or synthesis scheme, the residue R is a residue of the formula CH 3 - (CH 2 ) x = 0-28 - C(O) - denotes):

[0136] Furthermore, the present invention relates – according to a second Aspect of the present invention - a process for the production of functionalized, in particular fatty acid functionalized, polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), (A) wherein, according to a (first) synthesis route (A), in a first process step at least one compound of the general formula (I) CH 3 - C(O) - CH 2 - C(O)OR 1< (I) wherein in the general formula (I) the residue R 1< represents a C 1 - C 4 alkyl, in particular methyl or ethyl, preferably ethyl, is reacted with at least one polyglycerol of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) wherein in the general formula (IIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, is reacted, wherein the reaction is carried out in the absence of solvents and wherein the reaction is carried out in the presence of a catalyst, wherein the compound according to the general formula (IV) R 1< - OH (IV) is formed simultaneously during the reaction, wherein in the general Formula (IV) the residue R 1< a C 1 -C 4 -alkyl,in particular methyl or ethyl, preferably ethyl; wherein the compound according to general formula (IV) is continuously withdrawn from the reaction followed by a second process step, the second process step comprising (i) at least partial functionalization, in particular at least partial esterification, of remaining hydroxyl groups by means of at least one fatty acid and / or its ester or anhydride, in particular by means of at least one C5-C34 fatty acid and / or its ester or anhydride, preferably by means of at least one C8-C34 fatty acid and / or its ester or anhydride, and / or (ii) partial transesterification of ester groups introduced in the first process step by means of at least one fatty acid and / or its ester, in particular by means of at least one C5-C34 fatty acid and / or its ester, preferably by means of at least one C8-C34 fatty acid and / or its ester; , or(B) wherein, according to a (second, alternative to (A)) synthesis route (B), in a first process step, at least one polyglycerol of the general formula (IIb) HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] p - OH (IIb) where in the general formula (IIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, is reacted with at least one fatty acid and / or its ester or anhydride, in particular with at least one C 5 - C 34 fatty acid and / or its ester or anhydride, preferably with at least one C 8 - C 34 fatty acid and / or its ester or anhydride, is followed by a second process step, wherein the second process step (i) is an at least partial esterification of any remaining hydroxyl groups by means of a compound of the general formula (I), as defined above,and / or (ii) a partial transesterification of ester groups introduced in the first process step by means of a compound of general formula (I), as defined above; such that one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, preferably C8-C34 fatty acid-functionalized, 3-oxobuteric acid polyglycerol esters are obtained as reaction products.

[0137] In particular, the manufacturing process according to the invention can be carried out according to synthesis route (A) in accordance with the previously described process according to the invention.

[0138] In accordance with this aspect of the invention, it is also provided according to synthesis route (B) that the polyglycerols used in synthesis route (B) of the process according to the invention correspond to the general formula (IIb') HO - CH 2 - CH(OH) - CH 2 - [O - CH 2 - CH(OH) - CH 2 ] q - OH (IIb'), wherein in the general formula (IIb') the variable q is an integer from 0 to 6, in particular 0 to 4, preferably 0 or 1, particularly preferably 1.

[0139] According to a further particular embodiment of the inventive process according to synthesis route (B), the polyglycerol (IIb) can be a diglycerol of formula (IIc) HO - CH 2 - CH(OH) - CH 2 - O - CH 2 - CH(OH) - CH 2 - OH (IIc).

[0140] According to an alternative particular embodiment of the inventive process according to synthesis route (B), the polyglycerol (IIb) is not propane-1,2,3-triol (glycerol).

[0141] As regards the fatty acid and / or fatty acid ester that can be used in the process according to the invention via synthesis route (B), it is particularly preferred if the fatty acid and / or fatty acid ester is a carboxylic acid and / or a carboxylic acid ester of the general formula (VII) R 3< - O - R 4< (VII), wherein in the general formula (VII) the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -, and the residue R 4< is hydrogen or a C 1 -C 4 -alkyl, in particular hydrogen, methyl or ethyl, particularly preferably hydrogen.

[0142] As regards the fatty acid anhydride that can be used in the process according to the invention via synthesis route (B), it is particularly preferred if the fatty acid anhydride is a carboxylic acid anhydride of the general formula (V) R 3< - O - R 3< (V), wherein in the general formula (V) the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O) -, preferably (C 7 -C 33 -alkyl) - C(O) -.

[0143] In particular, in the process according to the invention, according to synthesis route (B), the reaction in the first process step is carried out in the absence of solvents and / or without any solvent at all. As explained above, this means that the reaction is carried out as a reaction in bulk, as a reaction in substance, or as a so-called Bulk ReactionThis has the advantage that the reaction products obtained are not contaminated with solvents, and no solvent needs to be removed, disposed of, or recycled in a costly and energy-intensive manner after the process or reaction. Surprisingly, the process or reaction still proceeds with high conversions and yields and, at least essentially, without significant byproduct formation.

[0144] According to a particular embodiment of the inventive process according to synthesis route (B), in the first process step the reaction can be carried out in the presence of a catalyst, in particular a metal-containing and / or metal-based, acidic or basic catalyst, if fatty acid and / or its esters are used as starting material.

[0145] In this context, it is particularly preferable if the catalyst is recycled after the conversion process.

[0146] Alternatively to this particular embodiment, according to synthesis route (B), the reaction is carried out in the absence of a catalyst and / or without a catalyst in the case of the use of fatty acid anhydride as a starting material.

[0147] As previously stated, according to a particular embodiment of the manufacturing process according to the invention, in the first process step, the reaction can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst if fatty acid and / or its esters are used as starting material.

[0148] The catalyst may be selected from (i) basic catalysts, in particular alkali or alkaline earth hydroxides and alkali or alkaline earth alcoholates, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe and Na(OBu-tert.), (ii) acidic catalysts, in particular mineral acids and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminum compounds, such as titanium tetrabutylate, stannic acids, zinc acetate, aluminum trichloride and aluminum triisopropyl, and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminum oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminas, as well as combinations thereof.

[0149] In this embodiment, an alkali or alkaline earth alcoholate can be used as a catalyst.

[0150] In this context, as mentioned previously, it is particularly preferable if the catalyst is recycled after the conversion process.

[0151] If, according to the particular embodiment, the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst, it is preferred if the reaction is carried out at temperatures in the range of 20 °C to 150 °C, in particular in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0152] In particular, according to this embodiment, it is also preferred if the catalyst is used in amounts, based on the total amount of the starting compounds, in the range of 0.01 wt.% to 30 wt.%, in particular in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, preferably in the range of 0.2 wt.% to 10 wt.%.

[0153] Furthermore, according to this embodiment, it is preferred if the reaction is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most especially at about 1 bar.

[0154] In the context of the manufacturing process according to the inventive synthesis route (B), when fatty acid and / or its esters are used as starting material, the compound of the general formula (VIII) R 4< - OH (VIII) is formed simultaneously during the reaction, wherein the residue R 4< has the meaning given above.

[0155] In this context, it is particularly preferred if the compound of general formula (VIII) is removed during or after the reaction, especially during the reaction, preferably by distillation.

[0156] In the context of the manufacturing process according to the inventive method via synthesis route (B), when fatty acid anhydride is used as a starting material, the compound of the general formula (VI) R 3< - OH (VI) is formed simultaneously during the reaction, wherein the residue R 3< has the meaning given above.

[0157] It is particularly preferred if the compound of general formula (VI) is removed during or after the reaction, preferably by distillation.

[0158] In particular, in the process according to the invention, the second process step is also carried out in the absence of solvents and / or without any solvent at all, according to synthesis route (B).

[0159] Furthermore, in the process according to the invention, the second process step is also carried out in the presence of a catalyst, in particular a metal-containing and / or metal-based, acidic or basic catalyst, according to synthesis route (B).

[0160] In this context, it is also preferable if the catalyst is recycled after the conversion process.

[0161] According to a particular embodiment of the present invention, it is preferred if the manufacturing process according to synthesis route (B) is also carried out in the second process step in the presence of a metal-containing and / or metal-based, acidic or basic catalyst.

[0162] In particular, according to this particular embodiment, it is also preferred if the catalyst is selected from (i) basic catalysts, especially alkali or alkaline earth hydroxides and alkali or alkaline earth alkoxides, such as NaOH, KOH, LiOH, Ca(OH)₂, NaOMe, KOMe, and Na(OBu-tert.), (ii) acidic catalysts, especially mineral acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acids, methanesulfonic acid, para-toluenesulfonic acid, and carboxylic acids, (iii) Lewis acids, especially Lewis acids based on titanium, tin, zinc, and aluminum compounds, such as titanium tetrabutylate, tin acids, zinc acetate, aluminum trichloride, and aluminum triisopropyl, and (iv) heterogeneous catalysts, especially based on mineral silicates, germanates, carbonates, and aluminum oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites, and Clays, and their combinations.

[0163] In this context, an alkali or alkaline earth alcoholate is used in particular as a catalyst.

[0164] As previously stated, it is particularly advantageous if the catalyst is recycled after esterification and / or transesterification.

[0165] According to this particular embodiment of the process according to the invention, the temperatures can vary over a wide range. In particular, according to synthesis route (B), the second process step can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at temperatures in the range of 20 °C to 150 °C, particularly in the range of 50 °C to 140 °C, preferably in the range of 70 °C to 130 °C, particularly preferably in the range of 80 °C to 125 °C, and most preferably in the range of 100 °C to 120 °C.

[0166] Furthermore, the amount of catalyst can also be varied according to this particular embodiment: The catalyst can be used in amounts, based on the total amount of the starting compounds, in the range of 0.01 wt.% to 30 wt.%, in particular in the range of 0.05 wt.% to 15 wt.%, preferably in the range of 0.1 wt.% to 15 wt.%, preferably in the range of 0.2 wt.% to 10 wt.%.

[0167] If, according to this particular embodiment of the present invention, the second process step is carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst according to synthesis route (B), the pressure range can likewise vary over a wide range: In particular, the second process step can be carried out in the presence of a metal-containing and / or metal-based, acidic or basic catalyst at a pressure in the range of 0.0001 bar to 10 bar, particularly in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, particularly preferably in the range of 0.05 bar to 1 bar, and most particularly at about 1 bar.

[0168] In this particular embodiment of the inventive process, the compound of general formula (IX) R 1< - O - R 5< (IX) is formed simultaneously in the second process step according to synthesis route (B), wherein in general formula (IX) the residue R 1< represents a C 1 -C 4 alkyl, in particular methyl or ethyl, preferably ethyl, and the residue R 5< each independently, of the same or different, represents hydrogen or a residue R 3< as previously defined.

[0169] In this context, it is particularly intended that the compound of general formula (IX) is removed during or after the reaction, especially during the reaction, preferably by distillation.

[0170] In the processes according to the first and second aspects of the invention, a fatty acid or its derivative, in particular an ester or anhydride, can be used in the functionalization or esterification or transesterification.

[0171] According to the invention, it is particularly provided that the fatty acid, preferably the C5-C34 fatty acid, in particular the C8-C34 fatty acid, especially in free form or in the form of its ester or anhydride, is selected from the group consisting of caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid, lacceric acid, geddic acid, undecylenic acid, myristoleic acid, palmitoleic acid, margaroleic acid, petroselinic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, cetoleic acid, erucic acid, nervonic acid, linoleic acid, linolenic acids, calendic acid, punicic acid, and eleostearic acids. Stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, and tetracosahexaenoic acid, as well as mixtures thereof.

[0172] According to a particular embodiment of the present invention, it is preferred that the fatty acid, preferably the C5-C34 fatty acid, in particular the C8-C34 fatty acid, especially in free form or in the form of its ester or anhydride, is selected from the group consisting of myristic acid, pentadecanoic acid, palmitoleic acid, cetoleic acid, oleic acid, gadoleic acid, cetoleic acid, erucic acid, arachidonic acid, eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosahexaenoic acid, and mixtures thereof, preferably eicosapentaenoic acid and docosahexaenoic acid, and mixtures thereof.

[0173] According to a further particular embodiment, the fatty acid, preferably the C 5 -C 34 fatty acid, in particular the C 8 -C 34 fatty acid, especially in free form or in the form of its ester or anhydride, is selected from the group of fish oil-based and / or fish oil-containing fatty acids, in particular eicosapentaenoic acid, docosadienoic acid, docosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid and tetracosahexaenoic acid, as well as mixtures thereof, preferably eicosapentaenoic acid, docosahexaenoic acid, as well as mixtures thereof.

[0174] Within the framework of the process(s) according to the two aforementioned aspects of the invention, one or more optionally functionalized, preferably optionally fatty acid functionalized, preferably optionally C 5 -C 34 fatty acid functionalized, preferably optionally C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters can be obtained as reaction products.

[0175] In particular, one or more 3-oxobutyric acid polyglycerol esters can be obtained as a reaction product within the framework of the process according to the first aspect of the invention.

[0176] Furthermore, within the framework of the process according to the first or second aspect of the invention, one or more functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, particularly preferably C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters can be obtained as a reaction product.

[0177] Furthermore, the present invention relates – according to a thirdAn aspect of the present invention is an optionally functionalized 3-oxobutyric acid polyglycerol ester or a mixture of at least two different optionally functionalized 3-oxobutyric acid polyglycerol esters obtainable according to the method of the present invention. In particular, these are one or more optionally functionalized, especially optionally fatty acid-functionalized, preferably optionally C5-C34 fatty acid-functionalized, more preferably optionally C8-C34 fatty acid-functionalized, polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid or 3-oxobutanoic acid) or mixtures thereof.

[0178] According to a particular embodiment of the present invention, the reaction product can comprise one or more optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C 5 -C 34 fatty acid-functionalized, preferably optionally C 8 -C 34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters of the general formula (IIIb 1 ") R 6< O - CH 2 - CH(OR 6< ) - CH 2 - [O - CH 2 - CH(OR 6< ) - CH 2 ] p - OR 6< (IIIb 1 "), wherein in the general formula (IIIb 1 ") where the variable p is an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< is each independently, identically or differently, representing: hydrogen, CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< , wherein the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 - C 33 -alkyl) - C(O) -, in particular (C 4 - C 33 -alkyl) - C(O) -, preferably (C 7 - C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen. and with the proviso that at least one residue R 6< , in particular at least two residues R 6< CH 3 - C(O) - CH 2 - C(O) - represents.

[0179] According to a further particular embodiment of the present invention, the reaction product can comprise one or more optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C5-C34 fatty acid-functionalized, preferably optionally C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters of the general formula (IIIc) R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc)), wherein in the general formula (IIIc) the residue R6< is, independently of one another, the same or different, hydrogen, CH3-C(O)-CH2-C(O)- or a residue R3<, wherein the residue R3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33 alkyl)-C(O)-, in particular (C 4-C33-alkyl)-C(O)-, preferably (C7-C33-alkyl)-C(O)-, but with the proviso thatthat at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen, , and with the proviso that at least one residue R 6< , in particular at least two residues R 6< CH 3 - C(O) - CH 2 - C(O) - represents.

[0180] According to a particular embodiment of the present invention, the reaction product may in particular comprise a mixture of at least two different, optionally functionalized, preferably optionally fatty acid functionalized, in particular optionally C 5 -C 34 fatty acid functionalized, preferably optionally C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0181] According to a further particular embodiment of the present invention, the reaction product may in particular comprise a mixture of at least three different, optionally functionalized, preferably optionally fatty acid functionalized, in particular optionally C 5 -C 34 fatty acid functionalized, preferably optionally C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0182] In the event that no functionalization, esterification, or transesterification is carried out, one or more 3-oxobutyric acid polyglycerol esters are obtained as the reaction product (i.e., (chemical) product or product mixture).

[0183] In particular, the reaction product may comprise one or more 3-oxobutyric acid polyglycerol esters of the general formula (IIIb) R 2< O - CH 2 - CH(OR 2< ) - CH 2 - [O - CH 2 - CH(OR 2< ) - CH 2 ] p - OR 2< (IIIb), wherein in the general formula (IIIb) the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, the residue R 2< each independently of each other, the same or different, represents: hydrogen or CH 3 - C(O) - CH 2 - C(O) -, however with the proviso that at least one residue R 2< , in particular at least two residues R 2< , does not represent hydrogen.

[0184] According to a particular embodiment of the present invention, the reaction product can comprise one or more 3-oxobutyric acid polyglycerol esters of the general formula (IIIc) R 2< O - CH 2 - CH(OR 2< ) - CH 2 - O - CH 2 - CH(OR 2< ) - CH 2 - OR 2< (IIIc), wherein in the general formula (IIIc) the residue R 2< represents, independently of each other, the same or different, hydrogen or CH 3 - C(O) - CH 2 - C(O) -, but with the proviso that at least one residue R 2< , in particular at least two residues R 2< , does not represent hydrogen.

[0185] According to a particular embodiment, the reaction product may in particular comprise a mixture of at least two different 3-oxobutyric acid polyglycerol esters, especially as defined above.

[0186] In particular, the mixture may have a weight-related ratio of monoglyceride esters / di- and higher glyceride esters in the range of 15-70 / 30-85, especially in the range of 20-65 / 35-80.

[0187] According to a further particular embodiment, the reaction product may in particular comprise a mixture of at least three different 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0188] In particular, the mixture may have a weight-related ratio of monoglyceride esters / diglyceride esters / triglyceride and higher glyceride esters in the range of 15-50 / 35-60 / 1-35, especially in the range of 20-45 / 40-55 / 3-30.

[0189] In the event that functionalization, esterification, or transesterification is carried out, one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, especially C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters are obtained as the reaction product (i.e., (chemical) product or product mixture). According to a particular embodiment of the present invention, the reaction product can comprise one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, particularly preferably C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters of the general formula (IIIb 1 ') R 6< O - CH 2 - CH(OR 6< ) - CH 2 - [O - CH 2 - CH(OR 6< ) - CH 2 ] p - OR 6< (IIIb 1 '), wherein in the general formula (IIIb 1 ') where the variable p is an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< is each independently, identically or differently, representing: hydrogen, CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< as defined above, but with the proviso that at least two residues R 6< do not represent hydrogen. and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , CH 3 - C(O) - CH 2 - C(O) - represents, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 3< , as previously defined.

[0190] In particular, in the general formula (IIIb 1 '), the residue R 6< can each be independent, the same, or different: CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents CH 3 - C(O) - CH 2 - C(O) - , and provided that at least one remainder R 6< represents a remainder R 3< as defined above.

[0191] It is particularly preferred if, in the general formula (IIIb 1 '), the residue R 6< does not represent hydrogen, whether it is the same or different from each other.

[0192] According to a further particular embodiment of the present invention, the reaction product can comprise one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, particularly preferably C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters of the general formula (IIIc') R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc'), wherein in the general formula (IIIc') the residue R6< represents, independently of one another, the same or different: hydrogen, CH3-C(O)-CH2-C(O)- or a residue R3< as defined above, but with the proviso that at least two residues R6< do not represent hydrogen. and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , CH 3 -C(O) - CH 2 - C(O) - represents, andwith the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 3< , as previously defined.

[0193] In particular, in the general formula (IIIc') the residue R 6< can each be independent, the same or different: CH 3 - C(O) - CH 2 -C(O) - or a residue R 3< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents CH 3 - C(O) - CH 2 - C(O) - , and provided that at least one remainder R 6< represents a remainder R 3< as defined above.

[0194] It is particularly preferred if, in the general formula (IIIc'), the residue R 6< does not represent hydrogen, whether independently of each other, the same or different.

[0195] According to a particular embodiment, the reaction product may in particular comprise a mixture of at least two different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, particularly preferably C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0196] According to a further particular embodiment, the reaction product may in particular comprise a mixture of at least three different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, particularly preferably C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0197] Another object of the present invention is also an optionally functionalized 3-oxobutyric acid polyol ester (III"), in particular as defined above, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C 5 -C 34 fatty acid-functionalized, preferably optionally C 8 -C 34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester of the general formula (IIIb 1 ") R 6< O - CH 2 - CH(OR 6< ) - CH 2 - [O - CH 2 - CH(OR 6< ) - CH 2 ] p - OR 6< (IIIb 1 ") corresponds to the general formula (IIIb 1 ") where the variable p is an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, and the residue R 6< is each independently, identically or differently, representing: hydrogen, CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< , wherein the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 - C 33 -alkyl) - C(O) -, in particular (C 4 - C 33 -alkyl) - C(O) -, preferably (C 7 - C 33 -alkyl) - C(O) -, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , does not represent hydrogen. and with the proviso that at least one residue R 6< , in particular at least two residues R 6< CH 3 - C(O) - CH 2 - C(O) - represents.

[0198] A further object of the present invention is also an optionally functionalized 3-oxobutyric acid polyol ester (III"), in particular as defined above, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C 5 -C 34 fatty acid-functionalized, preferably optionally C 8 -C 34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester of the general formula (IIIc) corresponds to R 6< O - CH 2 - CH(OR 6< ) - CH 2 - O - CH 2 - CH(OR 6< ) - CH 2 - OR 6< (IIIc)), wherein in the general formula (IIIc) the residue R 6< represents, independently of one another, the same or different: hydrogen, CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< , wherein the residue R 3< is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C 1 -C 33 -alkyl) - C(O) -, in particular (C 4 -C 33 -alkyl) - C(O)⁻, preferably (C₇-C₃³-alkyl)⁻C(O)⁻, but with the proviso that at least one residue R⁶<, in particular at least two residues R⁶<, does not represent hydrogen, andwith the proviso that at least one residue R 6< , in particular at least two residues R 6< CH 3 - C(O) - CH 2 - C(O) - represents.

[0199] A further object of the present invention according to this aspect of the invention is, according to a particular embodiment, a mixture comprising at least two different, optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C 5 -C 34 fatty acid-functionalized, preferably optionally C 3 -C 34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0200] A further object of the present invention according to this aspect of the invention is, according to a particular embodiment, a mixture comprising at least three different, optionally functionalized, preferably optionally fatty acid-functionalized, in particular optionally C 5 -C 34 fatty acid-functionalized, preferably optionally C 8 -C 34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0201] According to a further embodiment, a further object of the present invention is a 3-oxobutyric acid polyglycerol ester, in particular as defined above, wherein the 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIb) R 2< O - CH 2 - CH(OR 2< ) - CH 2 - [O - CH 2 - CH(OR 2< ) - CH 2 ] p - OR 2< (IIIb) wherein in the general formula (IIIb) • the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, • the residue R 2< represents, independently of each other, the same or different: hydrogen or CH 3 - C(O) - CH 2 - C(O) -, however with the proviso that at least one residue R 2< , in particular at least two residues R 2< , does not represent hydrogen.

[0202] According to this embodiment, a further object of the present invention is a 3-oxobutyric acid polyglycerol ester, in particular as defined above, wherein the 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIc) R 2< O - CH 2 - CH(OR 2< ) - CH 2 - O - CH 2 - CH(OR 2< ) - CH 2 - OR 2< (IIIc), wherein in the general formula (IIIc) the residue R 2< represents, independently of each other, the same or different, hydrogen or CH 3 - C(O) - CH 2 - C(O) -, but with the proviso that at least one residue R 2< , in particular at least two residues R 2< , does not represent hydrogen.

[0203] Another object of the present invention according to this aspect of the invention, in accordance with a further particular embodiment, is a mixture comprising at least two different 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0204] In particular, the mixture may have a weight-related ratio of monoglyceride esters / di- and higher glyceride esters in the range of 15-70 / 30-85, especially in the range of 20-65 / 35-80.

[0205] A further object of the present invention according to this aspect of the invention, in accordance with a further particular embodiment, is a mixture comprising at least three different 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0206] In particular, the mixture may have a weight-related ratio of monoglyceride esters / di- and higher glyceride esters in the range of 15-50 / 35-60 / 1-35, especially in the range of 20-45 / 40-55 / 3-30.

[0207] According to a further embodiment, a further object of the present invention is a functionalized 3-oxobutyric acid polyglycerol ester, in particular as defined above, wherein the functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, particularly preferably C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIb 1 ') R6< O-CH2-CH(OR6< )-CH2-[O-CH2-CH(OR6< )-CH2]p-OR6< (IIIb 1 '), wherein in the general formula (IIIb 1 ') • the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, particularly preferably 1, • the residue R6< represents, independently of one another, the same or different: hydrogen, CH3-C(O)-CH2-C(O)- or a residue R3< , as defined above, but with the proviso that at least two residues R6< do not represent hydrogen, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< , CH 3 - C(O) - CH 2 - C(O) - represents, andwith the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 3< , as previously defined.

[0208] In particular, in the general formula (IIIb 1 '), the residue R 6< can each be independent, the same, or different: CH 3 - C(O) - CH 2 - C(O) - or a residue R 3< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents CH 3 - C(O) - CH 2 - C(O) - , and provided that at least one remainder R 6< represents a remainder R 3< as defined above.

[0209] In this particular embodiment, it is preferred if, in the general formula (IIIb 1 '), the residue R 6< does not represent hydrogen, whether different or identical, independently of each other.

[0210] According to this particular embodiment, a further object of the present invention is a functionalized 3-oxobutyric acid polyglycerol ester, in particular as defined above, wherein the functionalized, in particular fatty acid-functionalized, preferably C5-C34 fatty acid-functionalized, particularly preferably C8-C34 fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIc') R6< O-CH2-CH(OR6< )-CH2-O-CH2-CH(OR6< )-CH2-OR6< (IIIc'), wherein in the general formula (IIIc') the residue R6< represents, independently of one another, the same or different: hydrogen, CH3-C(O)-CH2-C(O)- or a residue R3< , as defined above, but with the proviso that at least two residues R6< do not represent hydrogen, and with the proviso that at least one residue R 6< , in particular at least two residues R 6< represents CH 3 -C(O)-CH 2 -C(O)- , andwith the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents a residue R 3< , as previously defined.

[0211] In particular, in the general formula (IIIc') the residue R 6< can each be independent, the same or different: CH 3 -C(O)-CH 2 -C(O) - or a residue R 3< , as defined above, but with the proviso that at least one residue R 6< , in particular at least two residues R 6< , represents CH 3 -C(O)-CH 2 -C(O)- , and provided that at least one remainder R 6< represents a remainder R 3< as defined above.

[0212] In this particular embodiment, it is preferred if, in the general formula (IIIc'), the residue R 6< does not represent hydrogen, whether independently of each other, the same or different.

[0213] A further object of the present invention according to this aspect of the invention is, according to a further particular embodiment, a mixture comprising at least two different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, particularly preferably C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0214] A further object of the present invention according to this aspect of the invention is, according to a further particular embodiment, a mixture comprising at least three different functionalized, in particular fatty acid functionalized, preferably C 5 -C 34 fatty acid functionalized, particularly preferably C 8 -C 34 fatty acid functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

[0215] As the applicant has surprisingly discovered, the 3-oxobutyric acid polyglycerol ester obtainable or optionally functionalized according to the inventive manufacturing process, as defined above, is particularly suitable as a precursor or metabolite of the ketone bodies acetoacetate (acetate acetate) and ultimately 3-hydroxybutyric acid or its salts, since this precursor or metabolite is physiologically converted, particularly in the gastrointestinal tract, to acetoacetate (acetate acetate) and ultimately to 3-hydroxybutyric acid or its salts, and simultaneously exhibits good physiological compatibility and tolerability, especially with regard to non-toxicity and acceptable organoleptic properties. In particular, the sustained release of the physiologically active substance (i.e.,Acetoacetate and ultimately 3-hydroxybutyric acid in the gastrointestinal tract is advantageous in the medical field because the active ingredient 3-hydroxybutyric acid can be made available over a longer period, thus enabling ketosis therapy. 3-Oxobutyric acid polyglycerol esters have a more delayed-release effect than 3-hydroxybutyric acid polyol esters, which further extends the period of drug release in such therapy compared to the use of 3-hydroxybutyric acid polyol esters.

[0216] Furthermore, the 3-oxobutyric acid polyglycerol ester or ester obtained according to the inventive manufacturing process or optionally functionalized according to the inventive process, as defined above, is readily accessible or available synthetically on an industrial scale, and also with the required pharmaceutical or pharmacological quality.

[0217] The 3-oxobutyric acid polyglycerol ester or esters obtained according to the manufacturing process according to the invention, or optionally functionalized according to the invention, as defined above, thus represents an efficient pharmacological drug target in the context of ketone body therapy of the human or animal body.

[0218] The remaining aspects of the invention will be explained in more detail below.

[0219] Likewise, the present invention relates – according to a fourth Aspect of the present invention - a pharmaceutical composition, in particular a drug or medicament, which comprises one or more 3-oxobuteric acid polyglycerol esters obtainable by the manufacturing process according to the invention and / or optionally functionalized according to the invention, as defined above.

[0220] In particular, according to this aspect of the invention, the present invention relates to a pharmaceutical composition for the prophylactic and / or therapeutic treatment of diseases of the human or animal body. These may include, in particular, diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV,rheumatic diseases such as rheumatoid arthritis and gout, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy.

[0221] Furthermore, the 3-oxobutyric acid polyglycerol ester obtainable according to the inventive manufacturing process and / or optionally functionalized according to the inventive process, as defined above, is suitable for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as, in particular, traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defect, Huntington's disease,Cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and gout, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy.

[0222] Furthermore, the use of one or more optionally functionalized 3-oxobutyric acid polyglycerol esters obtainable according to the inventive manufacturing process or as defined above, can be used for the prophylactic and / or therapeutic treatment or for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disturbance of energy metabolism, especially ketone body metabolism, such as in particular traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defect,Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and gout, gastrointestinal diseases such as chronic inflammatory bowel diseases, especially ulcerative colitis and Crohn's disease, lyosomal storage diseases such as sphingolipidoses, especially Niemann-Pick disease, diabetes mellitus and effects or side effects of chemotherapy, may be included.

[0223] Furthermore, the use of one or more optionally functionalized 3-oxobutyric acid polyglycerol esters obtainable according to the inventive manufacturing process or as defined above can be intended for prophylactic and / or therapeutic treatment or for the manufacture of a medicament for prophylactic and / or therapeutic treatment or for use in / during catabolic metabolic states, such as hunger, diets or low-carbohydrate diets.

[0224] Furthermore, the present invention relates – according to a fifth Aspect of the present invention - a food and / or food product comprising one or more 3-oxobutyric acid polyglycerol esters, as defined above, which are optionally functionalized according to the manufacturing process or according to the invention.

[0225] According to a particular embodiment, the food and / or food product may in particular be a food supplement, a functional food ( Functional Food ), a Novel Food It could be a food additive, a nutritional supplement, a dietary food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0226] Finally, the use of one or more optionally functionalized 3-oxobutyric acid polyglycerol esters, as defined above, obtainable according to the manufacturing process according to the invention, in a food and / or food product may be provided.

[0227] The food and / or food product may be a food supplement, a functional food ( Functional Food ) , a Novel FoodIt could be a food additive, a nutritional supplement, a dietary food, a power snack, an appetite suppressant, or a strength and / or endurance sports supplement.

[0228] Further embodiments, modifications and variations of the present invention are readily apparent or feasible to the person skilled in the art when reading the description, without leaving the scope of the present invention.

[0229] The present invention is illustrated by the following exemplary embodiments, which are not intended to limit the present invention in any way, but merely to explain the exemplary and non-limiting implementation and design of the present invention. EXAMPLES OF EXECUTION: Abbreviations used

[0230] PG(2) = Diglycerol: HO-CH 2 -CH(OH)-CH 2 -O-CH 2 -CH(OH)-CH 2 -OH PG(3) = Polyglycerol: HO-CH 2 -CH(OH)-CH 2 -[O-CH 2 -CH(OH)-CH 2 ] 2 -OH Production examples

[0231] The manufacturing process according to the invention is illustrated by the following exemplary embodiments. The corresponding general reaction scheme is presented and explained in the general description section. Preparation of 3-oxobutyric acid diglycerol ester mixtures

[0232] In a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 25 g of ethyl 3-oxobutyric acid ester (ethyl acetoacetate or acetoacetic ester) and 6.5 g of diglycerin are placed.

[0233] At a temperature of 50 °C, 0.35 g of immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica, e.g. Novozym® (< 435) is added. The reaction mixture is stirred at 50 °C for 24 h. The enzyme is then filtered off and the excess ethyl 3-oxobutyrate is distilled off under vacuum.

[0234] The resulting reaction product is a 3-oxobutyric acid diglycerol ester and, according to analytical investigation, consists of the following composition: mono-3-oxobutyric acid diglycerol ester 45%, di-3-oxobutyric acid diglycerol ester 48%, tri-3-oxobutyric acid diglycerol ester 7%. Characterization is carried out by GC, GPC, and GC-MS.

[0235] During purification, reactants and reaction byproducts are removed, resulting in a pure mixture. A portion of the mixture undergoes separation by chromatography to obtain the various diglycerol esters as pure substances (i.e., pure mono-3-oxobutyric acid diglycerol ester, pure di-3-oxobutyric acid diglycerol ester, and pure tri-3-oxobutyric acid diglycerol ester). Another portion of the mixture undergoes separation by fractional distillation. Further preparation of 3-oxobutyric acid diglycerol ester mixtures

[0236] In a 250 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 106 g of ethyl 3-oxobutyric acid ester (ethyl acetoacetate or acetoacetic ester) and 29 g of diglycerin are placed.

[0237] At a temperature of 100 °C, 1.4 g of 30% methanolic NaOMe solution are added while stirring. The ethanol formed during the reaction is continuously distilled off. After a reaction time of 5 h, the reaction mixture is cooled and washed with NaCl solution. The crude ester mixture is then dried, and the excess ethyl 3-oxobutyric acid ester is distilled off under vacuum.

[0238] The reaction product is a 3-oxobutyric acid diglycerol ester with the following composition: mono-3-oxobutyric acid diglycerol ester 26%, di-3-oxobutyric acid diglycerol ester 51%, tri-3-oxobutyric acid diglycerol ester 22%, tetra-3-oxobutyric acid diglycerol ester 1%. Characterization is performed by GC, GPC, and GC-MS.

[0239] During purification, reactants and reaction byproducts are removed, resulting in a pure mixture. A portion of the mixture undergoes separation by chromatography to obtain the various diglycerol esters as pure substances (i.e., pure mono-3-oxobutyric acid diglycerol ester, pure di-3-oxobutyric acid diglycerol ester, pure tri-3-oxobutyric acid diglycerol ester, etc.). Another portion of the mixture undergoes separation by fractional distillation. Further preparation of 3-oxobutyric acid diglycerol ester mixtures

[0240] The preceding experiments are repeated (with enzyme and with NaOMe as catalyst), but with different polyols (namely with glycerol (not according to the invention), polyglycerol PG(3), and 1,2-pentanediol (not according to the invention)). Comparable results are obtained. Purification and fractionation are carried out in the same manner. Further manufacturing examples

[0241] Various polyol components based on polyhydric alcohols (polyols) are enzymatically reacted with 3-oxobutyric acid ethyl ester (ethyl acetoacetate or acetoacetic ester).

[0242] The polyols used are 1,2-pentanediol (not according to the invention) and diglycerol PG(2). The respective polyols are treated at 70 °C for 24 h with immobilized enzyme (CALB lipase on a polymer support, derived from Candida antarctica, For example, Novozym®< 435 from Sigma-Aldrich or Merck) is used (1 wt% enzyme and 40 mol% excess ethyl 3-oxobutyrate). The aforementioned polyols 1,2-pentanediol and diglycerol PG(2) are efficiently converted to the desired products with the aforementioned enzyme (Novozym®< 435). Results comparable to those obtained in previous experiments are performed in the same manner. Purification and separation or fractionation are carried out in the same way.

[0243] The experiments are repeated using sodium methoxide (NaOMe) as a catalyst instead of the enzyme and at temperatures between 100 and 120 °C. Comparable results are obtained. Purification and separation or fractionation are carried out in the same manner.

[0244] Since the 3-oxobutyric acid PG(2) esters in particular have only a slightly bitter taste, these esters are a particularly efficient product group for therapeutic applications. Therefore, the preceding experiment with enzyme and diglycerol PG(2) as a polyol will be carried out on a larger scale (2 to 4 kg).

[0245] Initially, the stoichiometric reaction conditions of the previous experiments are applied on a 2 kg scale (40 mol% excess of ethyl 3-oxobutyrate, 1 wt% enzyme). After 15 h, a portion of the reaction mixture (approx. 200 g) is removed for further analysis. This sample is a mono / di-PG(2) ester mixture. Subsequently, approximately 1 kg of ethyl 3-oxobutyrate is added. The aim is to synthesize a complete ester. It can be observed that after about 20 to 30 h, a constant concentration of di-PG(2) ester is established; the mono-PG(2) ester content decreases, and the tri-PG(2) ester content increases. Further analyses (GPC) show that a tetra-PG(2) ester has also formed.

[0246] After distilling off excess 3-oxobutyric acid ethyl ester, the initially obtained (low-boiling) mono / di-PG(2) ester mixture has only a slightly bitter taste, while the higher-boiling di- / tri- / tetra-PG(2) ester mixture has a somewhat stronger bitter taste. However, both mixtures are organoleptically acceptable and compatible.

[0247] After further purification, removing residual starting materials and reaction by-products, a pure mixture with significantly improved organoleptic properties is obtained. Attempts at functionalization

[0248] 1. Production of the anhydrideIn a 2000 mL multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 860 g of heptanoic acid are placed, and 445 g of acetic anhydride are added dropwise while stirring at 90 °C. The reaction mixture is stirred under reflux at 130 °C for 6 h. Subsequently, the acetic acid formed, as well as the excess acetic anhydride, are distilled off under vacuum. A heptanoic acid / heptanoic anhydride mixture with the following composition is obtained: 15% heptanoic acid, 85% heptanoic anhydride. Characterization is carried out by GC, GPC, and GC-MS. FunctionalizationIn a 100 ml multi-necked flask equipped with a dephlegmator (partial condenser) and distillation bridge, 25 g of heptanoic anhydride and 5 g of a 3-oxobuteric acid mono-, di-, tri-, tetra-diglycerol mixture prepared according to the invention are placed. The reaction mixture is stirred at 70 °C for 24 h. Subsequently, the excess heptanoic anhydride and the heptanoic acid formed are distilled off by short-path distillation. A 3-oxobuteric acid-heptanoic acid diglycerol ester mixture is obtained.

[0249] Comparable functionalization experiments are also carried out with fatty acids and alternatively fatty acid anhydrides and again alternatively fatty acid esters (each with eicosapentaenoic acid / docosahexaenoic acid mixture and their anhydrides and esters as well as with oleic acid and its anhydride and ester) and each lead to analogous results (i.e. esterification of the free OH groups), as confirmed by corresponding analysis.

[0250] The experiments show that the intended functionalization by reaction with carboxylic acid anhydrides leads to the desired products (i.e. esterification of the free OH groups), as confirmed by appropriate analysis. Further syntheses of functionalized 3-oxobutyric acid polyol esters

[0251] The polyols used are 1,2-pentanediol (not according to the invention) and diglycerol PG(2). The respective polyols are first reacted with sodium methoxide (NaOMe) as a catalyst and, at temperatures between 100 and 120 °C, with fatty acids and, alternatively, fatty acid anhydrides and, again alternatively, fatty acid esters (each with eicosapentaenoic acid and docosahexaenoic acid and their anhydrides and esters). This yields the corresponding fatty acid esterified polyols, which are then further reacted with ethyl 3-oxobutyric acid in a second, subsequent process step. This results in the corresponding 3-oxobutyric acid / fatty acid polyol ester mixtures. Comparable results are obtained by reversing the procedure (i.e., first reacting the polyols with ethyl 3-oxobutyric acid, followed by a further reaction with the aforementioned fatty acids or, alternatively, their anhydrides and esters). Physiological application trials: in - vitro -Digestion tests Digestion tests (cleavage or cleavage tests) of 3-oxobutyric acid-PG(2) ester mixtures according to the invention

[0252] Cleavage experiments show that 3-oxobutyric acid PG(2) esters or mixtures thereof, including reaction by-products, produced according to the invention can be cleaved in the human gastrointestinal tract.

[0253] The starting mixture used is, on the one hand, a purified mixture of mono-3-oxobutyric acid diglycerol ester, di-3-oxobutyric acid diglycerol ester, tri-3-oxobutyric acid diglycerol ester and tetra-3-oxobutyric acid diglycerol ester obtained according to the inventive process, and on the other hand, a purified mixture of functionalized mono-3-oxobutyric acid diglycerol ester, functionalized di-3-oxobutyric acid diglycerol ester and functionalized tri-3-oxobutyric acid diglycerol ester obtained according to the inventive process (see products from the functionalization experiments described above).

[0254] For the splitting experiments under conditions close to the body, two media are examined: FaSSGF, which simulates the stomach; FaSSIF, which simulates the intestinal tract.

[0255] Both media are from Biorelevant®, Ltd., UK. In some experiments, porcine pancreas (Panzytrat® 40,000, Allergan) is added to both media.

[0256] The results of hydrolysis experiments in a FaSSGF or FaSSIF medium with and without Panzytrat® (35 °C, 24 h each) show that the samples hydrolyze under FaSSGF conditions with and without Panzytrat®; this is mainly due to the low pH (pH = 1.6) of the medium. Under FaSSIF conditions, less conversion occurs when using Panzytrat®.

[0257] The experiment demonstrates that the starting mixture according to the invention represents a suitable physiological precursor for the ketone bodies acetoacetate and ultimately 3-hydroxybutyric acid for use in the corresponding ketone body therapies. Further digestion tests (cleavage tests) of 3-oxobutyric acid-PG(2) ester mixtures according to the invention Splitting experiments with pancreatin

[0258] 2 g of a mixture prepared as described above, based on mono-3-oxobutyric acid diglycerol esters, di-3-oxobutyric acid diglycerol esters, tri-3-oxobutyric acid diglycerol esters, and tetra-3-oxobutyric acid diglycerol esters, are dissolved in 50 g of water and mixed with 0.5 g (1 wt%) of pancreatin. The pancreatin is in the form of the commercially available product Panzytrat® < 40,000 from Allergan. The mixture is stirred on a hot plate at 50 °C; the reaction progress is determined and monitored by continuously measuring the acid number over time. The acid number increases over the observation period (decomposition of the 3-oxobutyric acid diglycerol ester mixture). The conversion / time profile of the aqueous cleavage of the ester mixture according to the invention using pancreatin, including the increase in acid number over time, demonstrates the desired decomposition of the starting material mixture. This is confirmed by appropriate analytical methods.This experiment also demonstrates that the starting mixture according to the invention represents a suitable physiological precursor for the ketone bodies acetoacetate and ultimately 3-hydroxybutyric acid for use in the corresponding ketone body therapies. The experiment is repeated and verified using each of the individual esters in pure form. Comparable results are obtained, i.e., the mono-3-oxobutyric acid diglycerol ester, the di-3-oxobutyric acid diglycerol ester, the tri-3-oxobutyric acid diglycerol ester, and the tetra-3-oxobutyric acid diglycerol ester are all cleaved by pancreatin. Further digestion tests (cleavage tests) of further 3-oxobutyric acid-polyol ester mixtures according to the invention

[0259] Furthermore, the other polyol ester mixtures of 3-oxobutyric acid produced according to the invention are also subjected to digestion tests in a corresponding manner, as described above, and yield analogous results.

[0260] The previously described cleavage experiments demonstrate that the polyol esters, especially polyglycerol esters, of 3-oxobutyric acid are efficient precursors or metabolites for the ketone bodies acetoacetate and ultimately 3-hydroxybutyric acid for use in the corresponding ketone body therapies, particularly with regard to their intended effect, which is also present in a physiologically tolerable or physiologically compatible form.

Claims

1. Method for the preparation of polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), wherein at least one compound of the general formula (I)         CH3-C(O)-CH2-C(O)OR1     (I) wherein, in the general formula (I), the residue R1 represents a C1-C4-alkyl, in particular methyl or ethyl, preferably ethyl, with at least one polyglycerol of the general formula (IIb)         HO-CH2-CH(OH)-CH2-[O-CH2-CH(OH)-CH2]p-OH     (IIb) wherein, in the general formula (IIb), the variable p represents an integer from 1 to 6, in particular from 1 to 4, preferably 1 or 2, and especially preferably 1, is reacted, wherein the reaction is carried out in the absence of solvents and wherein the reaction is carried out in the presence of a catalyst, so that one or more 3-oxobutyric acid polyglycerol esters are obtained as reaction products wherein, during the reaction, the compound according to the general formula (IV)         R1-OH     (IV) is formed, wherein in the general formula (IV) the residue R1 represents a C1-C4-alkyl, in particular methyl or ethyl, preferably ethyl, wherein the compound according to the general formula (IV) is continuously removed from the reaction.

2. Method according to claim 1, wherein the reaction is carried out in the presence of a catalyst, in particular an enzyme and / or a metal-containing, acidic or basic catalyst; and / or wherein the catalyst is recycled after the reaction.

3. Method according to claim 1 or claim 2, wherein hydroxyl groups still present in the reaction product after the reaction are at least partially, preferably completely, functionalized, in particular esterified; in particular wherein the functionalization, in particular esterification, of the hydroxyl groups still present in the reaction product after the reaction is carried out with at least one carboxylic acid anhydride of the general formula (V)         R3-O-R3     (V) wherein, in the general formula (V), the residue R3 is, independently of one another, identical or different, a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -.

4. Method according to claim 3, wherein the functionalization, in particular esterification, of the hydroxyl groups still present in the reaction product after the reaction is carried out by reaction with at least one carboxylic acid and / or a carboxylic acid ester of the general formula (VII)         R3-O-R4     (VII) wherein, in the general formula (VII) • the residue R3 represents a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, • the residue R4 represents hydrogen or a C1-C4-alkyl, in particular methyl or ethyl, preferably hydrogen.

5. Method according to claim 1 or claim 2, wherein the ester groups introduced into the reaction product (III) by the method according to claim 1 or claim 2 are subjected to partial transesterification using a compound of the general formula (VII) as defined above.

6. Method for the preparation of functionalized, in particular fatty acid-functionalized, polyglycerol esters of 3-oxobutyric acid (beta-oxobutyric acid, 3-oxobutanoic acid), (A) wherein, according to a (first) synthesis route (A), in a first step of the method at least one compound of the general formula (I)         CH3-C(O)-CH2-C(O)OR1     (I) wherein, in the general formula (I), the residue R1 represents a C1-C4-alkyl, in particular methyl or ethyl, preferably ethyl, with at least one polyglycerol of the general formula (IIb)         HO-CH2-CH(OH)-CH2-[O-CH2-CH(OH)-CH2]p-OH     (IIb) wherein, in the general formula (IIb), the variable p represents an integer from 1 to 6, in particular from 1 to 4, preferably 1 or 2, and especially preferably 1, is reacted, wherein the reaction is carried out in the absence of solvents and wherein the reaction is carried out in the presence of a catalyst, wherein the compound according to the general formula (IV)         R1-OH     (IV) is formed, wherein in the general formula (IV) the residue R1 represents a C1-C4-alkyl, in particular methyl or ethyl, preferably ethyl; wherein the compound according to the general formula (IV) is continuously removed from the reaction followed by a second step of the method, wherein the second step of the method comprises (i) at least partial functionalization, in particular at least partial esterification, of any remaining hydroxyl groups using at least one fatty acid and / or its ester or anhydride, in particular using at least one C5-C34-fatty acid and / or its ester or anhydride, preferably by means of at least one C8-C34-fatty acid and / or its ester or anhydride, and / or (ii) partial transesterification of ester groups introduced in the first step of the method using at least one fatty acid and / or its ester, in particular using at least one C5-C34-fatty acid and / or its ester, preferably using at least one C8-C34-fatty acid and / or its ester; or (B) wherein, according to a (second, alternative to (A)) synthesis route (B), in a first step of the method at least one polyglycerol of the general formula (IIb)         HO-CH2-CH(OH)-CH2-[O-CH2-CH(OH)-CH2]p-OH     (IIb) wherein, in the general formula (IIb), the variable p represents an integer from 1 to 6, in particular from 1 to 4, preferably 1 or 2, and especially preferably 1, with at least one fatty acid and / or its ester or anhydride, in particular with at least one C5-C34-fatty acid and / or its ester or anhydride, preferably with at least one C8-C34-fatty acid and / or its ester or anhydride, is reacted, followed by a second step of the method, wherein the second step of the method comprises (i) at least partial esterification of any remaining hydroxyl groups using a compound of the general formula (I) as defined above, and / or (ii) partial transesterification of ester groups introduced in the first step of the method using a compound of the general formula (I) as defined above; so that one or more functionalized, in particular fatty acid-functionalized, preferably C5-C34-fatty acid-functionalized, preferably C8-C34-fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters are obtained as reaction products.

7. Optionally functionalized 3-oxobutyric acid polyglycerol ester or mixture of at least two different, optionally functionalized 3-oxobutyric acid polyglycerol esters, obtainable according to the method according to one of the preceding claims.

8. Optionally functionalized 3-oxobutyric acid polyglycerol ester, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34-fatty acid-functionalized, in particular optionally C8-C34-fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIb1")         R6O-CH2-CH(OR6)-CH2-[O-CH2-CH(OR6)-CH2]p-OR6     (IIIb1") wherein, in the general formula (IIIb1") • the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, especially preferably 1, • the residue R6 independently of one another, identically or differently, represents: hydrogen, CH3-C(O)-CH2-C(O) - or a residue R3, wherein the radical R3 represents a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, but with the proviso that at least one residue R6,in particular at least two residues R6,does not represent hydrogen, and with the proviso that at least one residue R6, in particular at least two residues R6, represents CH3-C(O)-CH2-C(O)-.

9. Optionally functionalized 3-oxobutyric acid polyglycerol ester according to claim 8, wherein the optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34-fatty acid-functionalized, in particular optionally C8-C34-fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIc")         R6O- CH2-CH(OR6)-CH2-O-CH2-CH(OR6) -CH2-OR6     (IIIc") wherein, in the general formula (IIIc"), the residue R6 represents, independently of one another, the same or different: hydrogen, CH3 - C(O) - CH2 - C(O) - or a residue R3, wherein the residue R3 is a residue of the type linear (straight-chain) or branched, saturated or mono- or polyunsaturated (C1-C33-alkyl) - C(O) -, in particular (C4-C33-alkyl) - C(O) -, preferably (C7-C33-alkyl) - C(O) -, but with the proviso that at least one residue R6, in particular at least two residues R6, does not represent hydrogen, and with the proviso that at least one residue R6, in particular at least two residues R6, represents CH(3)- C(O) - CH2- C(O)-.

10. Optionally functionalized 3-oxobutyric acid polyglycerol ester according to claim 8, wherein the optionally functionalized 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIb)         R2O-CH2-CH(OR2)-CH2-[O-CH2-CH(OR2)-CH2]p-OR2.     (IIIb) wherein, in the general formula (IIIb), • the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, especially preferably 1, • the residue R2 represents, independently of one another, the same or different: hydrogen or CH3 - C(O) - CH2 - C(O) -, but with the proviso that at least one residue R2, in particular at least two residues R2, does not represent hydrogen.

11. Optionally functionalized 3-oxobutyric acid polyglycerol ester according to claim 8 or claim 10, 3-oxobutyric acid polyol ester (III) according to claim 10, wherein the optionally functionalized 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIc)         R2O-CH2-CH(OR2)-CH2-O-CH2-CH(OR2)-CH2-OR2     (IIIc) wherein, in the general formula (IIIc), the residue R2 represents, independently of one another, the same or different, hydrogen or CH3-C(O)-CH2-C(O) -, but with the proviso that at least one residue R2, in particular at least two residues R2, does not represent hydrogen.

12. Optionally functionalized 3-oxobutyric acid polyglycerol ester according to claim 8, wherein the optionally functionalized 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIb1')         R6O-CH2-CH(OR6)-CH2-[O-CH2-CH(OR6)-CH2]p-OR6     (IIIb1') wherein, in the general formula (IIIb1'), • the variable p represents an integer from 1 to 6, in particular 1 to 4, preferably 1 or 2, especially preferably 1, • the residue R6 represents, independently of one another, the same or different: hydrogen, CH3 - C(O) - CH2 - C(O) - or a residue R3 as defined above, but with the proviso that at least two residues R6 do not represent hydrogen, and with the proviso that at least one residue R6, in particular at least two residues R6, represents CH3 - C(O) - CH2 - C(O) -, and with the proviso that at least one residue R6, in particular at least two residues R6, represents a residue R3 as defined above.

13. Optionally functionalized 3-oxobutyric acid polyglycerol ester according to claim 8 or claim 12, wherein the optionally functionalized, in particular fatty acid-functionalized, preferably C5-C34-fatty acid-functionalized, particularly preferably C8 -C34 -fatty acid-functionalized, 3-oxobutyric acid polyglycerol ester corresponds to the general formula (IIIc')         R6O-CH2-CH(OR6)-CH2-O-CH2-CH(OR6)-CH2-OR6.     (IIIc') wherein, in the general formula (IIIc'), the residue R6 represents, independently of one another, the same or different: hydrogen, CH3-C(O) - CH(2) - C(O) - or a residue R3 as defined above, but with the proviso that at least two residues R6 do not represent hydrogen, and with the proviso that at least one residue R6, in particular at least two residues R6, represents CH3 - C(O) - CH2 - C(O) -, and provided that at least one residue R6, in particular at least two residues R6, represents a residue R3 as defined above.

14. Mixture comprising at least two, in particular at least three, mutually different, optionally functionalized, preferably optionally fatty acid-functionalized, preferably optionally C5-C34-fatty acid-functionalized, in particular optionally C8-C34-fatty acid-functionalized, 3-oxobutyric acid polyglycerol esters, in particular as defined above.

15. Pharmaceutical composition, in particular a drug or medication, comprising one or more optionally functionalized 3-oxobutyric acid polyglycerol esters according to any of claims 7 to 14.

16. Pharmaceutical composition according to claim 15 for use in the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with a disturbance of energy metabolism, in particular ketone body metabolism, such as in particular traumatic brain injury, stroke, hypoxia, cardiovascular diseases such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter defect (GLUT1 defect), VL-FAOD, and mitochondriopathies such as mitochondrial thiolase defect, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and gouty arthritis, diseases of the gastrointestinal tract such as chronic inflammatory bowel diseases, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipidoses, in particular Niemann-Pick disease, diabetes mellitus, and effects or side effects of chemotherapy.

17. Food and / or food product comprising one or more optionally functionalized 3-oxobutyric acid polyglycerol esters according to any of claims 7 to 14.