Process for the preparation of hydroxybutyric acid carboxylate

Abstract

This invention relates to a method for preparing 3-hydroxybutyric acid carboxylic acid esters (i.e., carboxylic acid esters of 4-oxo-2-butanol), particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylic acid esters, as well as the products obtained therefrom and their uses.

Description

Technical Field

[0001] This invention relates to the field of ketone bodies and related metabolism and the treatment of related diseases.

[0002] In particular, the present invention relates to a method for producing 3-hydroxybutyrate carboxylate, and the reaction product (i.e., 3-hydroxybutyrate carboxylate) obtained therefrom or prepared in this way, and its use, particularly in pharmaceutical compositions (e.g., drugs or pharmaceutical preparations) or in food and / or food products, and their further applications or uses.

[0003] Furthermore, the present invention relates to pharmaceutical compositions comprising reaction products (i.e., 3-hydroxybutyrate carboxylate) that can be obtained or produced according to the method of the present invention, particularly pharmaceuticals or medicaments, and their applications or uses.

[0004] Finally, the present invention relates to food and / or food products, particularly food supplements, functional foods, novel foods, food additives, dietary foods, energy snacks, appetite suppressants, and strength and / or endurance sports supplements, which contain reaction products (i.e., 3-hydroxybutyrate carboxylic acid esters) that can be obtained or produced according to the method of the present invention, and their applications or uses. Background Technology

[0005] In human energy metabolism, glucose is the short-term available energy carrier, metabolized into energy in the mitochondria by releasing water and carbon dioxide. The liver's glycogen reserves are depleted during nighttime sleep. However, the human central nervous system (CNS) and heart, in particular, require a permanent energy supply.

[0006] Physiological substitutes for glucose are so-called ketone bodies, which are primarily used in the central nervous system.

[0007] The term ketone bodies specifically refers to a collective term for three compounds that are primarily formed in catabolic states (such as starvation, reduced-weight diets, or low-carbohydrate diets) and can lead to ketosis. The term ketone bodies specifically includes three compounds: acetoacetate (synonymously also called acetoacetate), acetone, and 3-hydroxybutyric acid (hereinafter also synonymously called β-hydroxybutyric acid or BHB or 3-BHB) or a salt thereof (i.e., 3-hydroxybutyrate or β-hydroxybutyrate), the latter being the most important of the three compounds. 3-hydroxybutyric acid or its salts physiologically occur as (R)-enantiomers, i.e., as (R)-3-hydroxybutyric acid (synonymously also called (3R)-3-hydroxybutyric acid, to emphasize the chiral center at the 3-position) or a salt thereof.

[0008] These ketone bodies are also physiologically provided in large quantities by lipids stored in the body during fasting or starvation through fat breakdown, almost completely replacing glucose as an energy source.

[0009] Ketone bodies are formed in the liver from acetyl-CoA (=acetyl-CoA), which originates from β-oxidation; they represent a transportable form of acetyl-CoA in the body. However, in order to utilize ketone bodies, the brain and muscles must first adapt to the expression of the enzymes required to convert ketone bodies back into acetyl-CoA. Especially during periods of starvation, ketone bodies contribute significantly to energy production. For example, after a period of time, the brain can survive on only one-third of its daily glucose intake.

[0010] Physiologically, ketone bodies are synthesized from activated acetic acid in the form of two molecules of acetyl-CoA, a normal intermediate in fatty acid degradation. Acetyl-CoA is expanded using further acetyl-CoA units and the enzyme HMG-CoA synthase to the intermediate 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), in which HMG-CoA lyase ultimately cleaves acetoacetate. These three steps occur only in the mitochondria of the liver (Rainin cycle), where 3-hydroxybutyrate is ultimately formed in the cytosol via D-β-hydroxybutyrate dehydrogenase. HMG-CoA is also the end product of the degradation of the amino acid leucine, while acetoacetate is formed during the degradation of the amino acids phenylalanine and tyrosine.

[0011] Spontaneous decarboxylation converts acetoacetate into acetone; it can occasionally be detected in the breath of diabetics and dieters. It cannot be used further by the body. However, the proportion of acetone in ketone bodies is very small.

[0012] Therefore, acetoacetate is reduced to physiologically relevant forms of 3-hydroxybutyric acid or 3-hydroxybutyl ester, but it can also be broken down into physiologically unusable acetone and release carbon dioxide, which can be detected in the urine and exhaled air of patients with severe ketosis or ketoacidosis (e.g., in type 1 diabetes patients without insulin replacement).

[0013] 3-Hydroxybutyric acid is currently used and marketed in the field of weight training as a sodium, magnesium, or calcium salt.

[0014] However, from an evolutionary perspective, humans are unaware of 3-hydroxybutyric acid (HbA1c), or only in very small amounts, because plants do not produce HbA1c, and in animals, HbA1c is only found in emaciated animals that die from ketosis. Therefore, oral administration of HbA1c can cause nausea. The free acid form of HbA1c and its salts also taste bitter and can cause severe vomiting and nausea.

[0015] In addition, patients (especially newborns, but also adults) cannot tolerate large amounts of 3-hydroxybutyrate salts for extended periods, as these compounds can damage the kidneys.

[0016] Furthermore, 3-hydroxybutyric acid (3-Hydroxybutyric acid) and its salts have a very short plasma half-life. Even after taking several grams, ketosis only lasts for about three to four hours, meaning patients cannot continuously benefit from treatment with 3-Hydroxybutyric acid or its salts, especially at night. In cases of metabolic disorders, this can lead to life-threatening situations.

[0017] Therefore, in the treatment of such metabolic diseases, so-called medium-chain triglycerides, or MCTs, are currently used in ketogenic therapy, which is intended to be derived from the corresponding triglycerides of hexanoic acid, caprylic acid, and decanoic acid (i.e., saturated linear C6-, C8-, and C4-). 10 Metabolic transformation of fatty acids.

[0018] However, from a pharmaceutical and clinical perspective, 3-hydroxybutyric acid is essentially a more potent drug-pharmacological target molecule that, according to current technology, could in principle be used to treat a variety of diseases, but cannot be used due to a lack of physiological compatibility (e.g., diseases related to abnormalities in energy metabolism, particularly ketone body metabolism, or neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, etc., lipid metabolism disorders, etc.).

[0019] The following table shows only exemplary, and in no way limiting, potential therapeutic options or possible indications for the active ingredient 3-hydroxybutyric acid.

[0020]

[0021]

[0022] Therefore, from a pharmaceutical and clinical perspective, there is a desire to find effective precursors or metabolites that physiologically allow the direct or indirect acquisition of 3-hydroxybutyric acid or its salts, particularly in the physiological metabolism of humans or animals.

[0023] Therefore, there is no shortage of attempts in the prior art to find physiologically suitable precursors or metabolites of 3-hydroxybutyric acid or its salts. However, to date, no effective compounds have been found in the prior art. Furthermore, according to the prior art, obtaining such compounds is either impossible or not easily possible. Summary of the Invention

[0024] Therefore, the fundamental problem of the present invention is to provide an efficient method for producing physiologically suitable or physiologically compatible precursors and / or metabolites of 3-hydroxybutyric acid (i.e., β-hydroxybutyric acid, BHB, or 3-BHB) or its salts.

[0025] This method should in particular enable the efficient acquisition of the corresponding BHB precursors and / or BHB metabolites, especially in large quantities without significant amounts of toxic byproducts.

[0026] In a completely unexpected manner, the applicant has now discovered that 3-hydroxybutyric acid esters (3-hydroxybutyrate esters) represent effective and physiologically effective or physiologically compatible precursors and / or metabolites of ketone body 3-hydroxybutyric acid or its salts, and that efficient methods for producing these compounds have been found or developed herein, which allow for the direct and efficient, and particularly economical and industrially feasible, production of these compounds.

[0027] To address the aforementioned problems, according to a first aspect of the invention, the present invention therefore provides a method for producing 3-hydroxybutyric acid carboxylic acid ester according to claim 1; furthermore, particularly special and / or advantageous embodiments of the method of the invention are the subject of the relevant dependent claims.

[0028] Furthermore, according to a second aspect of the invention, the invention relates to a reaction product obtainable according to the inventive method of the independent claim (claim 28) or a 3-hydroxybutyric acid carboxylate according to the related claims (claims 34-37), or a mixture of at least two 3-hydroxybutyric acid carboxylates obtainable in this respect according to the corresponding claim (claim 38); furthermore, particularly special and / or advantageous embodiments of this aspect of the invention are the subject of the related dependent claims.

[0029] Similarly, according to a third aspect of the invention, the invention relates to pharmaceutical compositions, particularly pharmaceuticals or agents, according to the corresponding independent claim (claim 39); furthermore, particularly special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claims.

[0030] Furthermore, according to a fourth aspect of the invention, the present invention relates to the reaction product of the invention according to the corresponding independent claim (claim 41) or the 3-hydroxybutyric acid carboxylate of the invention or a mixture of at least two 3-hydroxybutyric acid carboxylates of the invention, for preventive and / or therapeutic treatment or for the prevention and / or therapeutic treatment of diseases in humans or animals.

[0031] Furthermore, according to a fifth aspect of the invention, the invention relates to the use of the reaction product of the invention according to the relevant independent claim (claim 42), or the 3-hydroxybutyric acid carboxylate of the invention, or a mixture of at least two 3-hydroxybutyric acid carboxylates of the invention, for preventive and / or therapeutic treatment or for the production of a medicament for the prevention and / or therapeutic treatment of diseases in humans or animals.

[0032] Furthermore, according to a sixth aspect of the invention, the invention relates to the use of the reaction product of the invention according to the relevant independent claim (claim 43), or the 3-hydroxybutyric acid carboxylate of the invention, or a mixture of at least two 3-hydroxybutyric acid carboxylates of the invention.

[0033] Furthermore, according to a seventh aspect of the invention, the invention relates to food and / or food products according to the relevant independent claim (claim 44); furthermore, particularly special and / or advantageous embodiments of food and / or food products according to the invention are the subject of the relevant dependent claims.

[0034] Finally, according to the eighth aspect of the invention, the invention relates to the use of the reaction product of the invention according to the relevant independent claim (claim 46) or the 3-hydroxybutyric acid carboxylate of the invention or a mixture of at least two 3-hydroxybutyric acid carboxylates of the invention in food and / or food products; furthermore, particularly special and / or advantageous embodiments of the use according to the invention are the subject of the relevant dependent claims.

[0035] It goes without saying that, in order to avoid repetition, the following description pertains to only one aspect of the invention. The following features, embodiments, advantages, etc., which are listed below, are also applicable to other aspects of the invention and need not be mentioned separately.

[0036] Furthermore, it goes without saying that various aspects and embodiments of the invention are also considered to be disclosed in any combination with other aspects and embodiments of the invention, and in particular any combination of features and embodiments, as they derive from the reverse reference of all patent claims, and are also considered to be a broad disclosure of all possible combinations.

[0037] Regarding all the relative or weight-based percentage data provided below, especially relative quantity or weight data, it should also be noted that, within the scope of this invention, these will be selected by those skilled in the art such that they always add up to 100% or 100 wt%, including all components or ingredients, particularly as defined below; however, this is self-evident to those skilled in the art.

[0038] Furthermore, if necessary, those skilled in the art may deviate from the following scope specifications without departing from the scope of this invention.

[0039] Furthermore, all values ​​or parameters specified below can, in principle, be determined or identified using standardized or explicitly defined determination methods or other determination or measurement methods familiar to those skilled in the art.

[0040] Having said all that, the invention will now be described in more detail:

[0041] Therefore, according to a first aspect of the invention, an object of the invention is to provide a method for preparing 3-hydroxybutyric acid carboxylic esters, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylic esters, wherein at least one of the general formula (I)(CH3-CH(OH)-CH2-C(O)OR1 (I) 3-hydroxybutyrate, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, reacts with at least one carboxylic acid (II), particularly with at least one carboxylic acid containing one or more carboxyl groups, preferably with at least one carboxylic acid containing two or more carboxyl groups, especially in esterification reactions and / or under esterification conditions, wherein, in general formula (I), group R 1 The expression represents a C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl, thereby obtaining one or more 3-hydroxybutyric acid carboxyl esters, particularly one or more carboxyl esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as reaction product (III).

[0042] According to the present invention, a method for producing 3-hydroxybutyric acid carboxylic acid ester is thus provided. 3-hydroxybutyrate ester may also be synonymously referred to as ethyl 3-hydroxybutyrate or alternatively as 4-oxo-2-butanol.

[0043] Strictly speaking, 3-hydroxybutyric acid of general formula (I) is (C1-C5 alkyl)-3-hydroxybutyrate (=3-hydroxybutyric acid (C1-C5 alkyl) ester), that is, the C1-C5 alkyl ester of 3-hydroxybutyric acid, which can also be synonymously called 4-oxo-4-(C1-C5-alkoxy)-2-butanol, or (hydroxy-C3-C5-alkyl)-3-hydroxybutyrate (=3-hydroxybutyric acid (hydroxy-C3-C5-alkyl) ester), that is, the hydroxy-C3-C5 alkyl ester of 3-hydroxybutyric acid, which can also be synonymously called 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0044] In this context, 3-hydroxybutyrate can be prepared by esterification of free 3-hydroxybutyric acid with the corresponding alcohol (e.g., a monool or diol). Hydroxybutyl-3-hydroxybutyrate (i.e., R...) 1 The synthesis of 3-hydroxybutyrate of general formula (I) of hydroxybutyl is schematically shown below:

[0045]

[0046] In addition, hydroxypentyl-3-hydroxybutyrate (i.e., R...) 1 The synthesis of 3-hydroxybutyrate of general formula (I) of hydroxypentyl group is schematically shown below:

[0047]

[0048] The preparation or synthesis of other 3-hydroxybutyrates is carried out in a similar manner.

[0049] In the method according to the invention, the starting compound or reactant 3-hydroxybutyrate of general formula (I) is used as an esterifying alcohol via the hydroxyl group at the 3-position and reacts with the carboxyl group of carboxylic acid (II) to form the corresponding 3-hydroxybutyric acid carboxylic ester as the reaction product (III), namely the carboxylic ester of the corresponding 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0050] In the context of this invention, the carboxylic acid (II) used is an organic carboxylic acid. That is, carboxylic acid (II) is an organic compound having one or more carboxyl groups (-COOH) and having acidic characteristics.

[0051] Surprisingly, the applicant has found a method for providing a sensorily compatible form of 3-hydroxybutyric acid or a derivative thereof, while still allowing for the easy release of 3-hydroxybutyric acid, particularly from animals or humans.

[0052] In addition, the applicant has successfully provided a sensory-compatible form of 3-hydroxybutyric acid in a manner that has a delayed effect; that is, 3-hydroxybutyric acid is released continuously over a longer period of time, particularly from human or animal bodies.

[0053] Furthermore, other cleavage products (i.e., cleavage products released along with or apart from 3-hydroxybutyric acid) can also be utilized by the body, or at least processed by the body. Specifically, cleavage products released are reactants, products, or intermediates of the citrate cycle, or their derivatives or salts, formed through the oxidation of reactants, products, or intermediates of the citrate cycle. Therefore, further cleavage products formed during the release of 3-hydroxybutyric acid can also be used as an energy source by the body or the human body. These cleavage products are typically carboxylic acids (II) or their salts or derivatives.

[0054] When a carboxylic acid with at least two free carboxyl groups is used, several 3-hydroxybutyrates may react with a carboxylic acid (i.e., several 3-hydroxybutyrates are added to a carboxylic acid, or a carboxylic acid is esterified with several 3-hydroxybutyrates), resulting in a high density of 3-hydroxybutyrates in a single molecule, and thus a high density of active ingredients.

[0055] As stated above, the applicant has found with great surprise that 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates prepared in this way are effective because physiologically compatible precursors and / or metabolites of 3-hydroxybutyric acid or its salts can also be used extensively in pharmaceutical or clinical applications due to their physiological compatibility.

[0056] The above-mentioned 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, which can be obtained for the first time in an efficient manner by the preparation method according to the invention, represent physiologically and pharmacologically relevant alternatives to free 3-hydroxybutyric acid or its salts.

[0057] The production of 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, via conventional organic synthesis is complex and expensive because 3-hydroxybutyric acid and its salts and esters tend to polymerize and undergo other undesirable side reactions (e.g., dehydration, decomposition, etc.). Within the scope of this invention, it is possible for the first time to provide an efficient method of preparation in which 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, can be produced, particularly in a single step, with at least substantially no undesirable side reactions.

[0058] Therefore, the method of the present invention enables, for the first time, the provision of non-toxic 3-hydroxybutyric acid carboxylates, particularly carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, from known, commercially available, and most importantly physiologically harmless components or reactants (starting compounds). The resulting 3-hydroxybutyric acid carboxylates, particularly carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, are physiologically decomposed, particularly in the stomach and / or intestine, releasing or generating the target molecule "3-hydroxybutyric acid" or its salts or esters as the active ingredient or active component.

[0059] In addition, the aforementioned 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, also contain an acceptable taste to ensure compatibility even when administered orally in larger doses over longer periods (e.g., 50g or more per day).

[0060] Similarly, the preparation method according to the invention can provide 3-hydroxybutyric acid carboxylic esters free of toxic impurities, particularly carboxylic esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0061] Furthermore, this method can also be carried out enantioselectively using suitable starting materials. For example, according to the invention, the preparation method allows for the enrichment of biologically relevant forms (i.e., (R)-enantiomers) through enzymatic catalysis or specific selection of starting compounds (reactants), thereby avoiding burden on the patient's renal system upon oral administration (i.e., elimination by the kidneys). However, in principle, enrichment of (S)-enantiomers is also feasible and may be useful under certain conditions.

[0062] Furthermore, the preparation method according to the present invention, including optional further processing or purification steps, can be operated economically and can also be implemented on a large scale.

[0063] In particular, the preparation method of the present invention uses commercially available starting compounds that can be synthesized by a simple process that can be carried out on a large scale and allows for relatively simple process management even on a large scale.

[0064] Compared to conventional preparation methods, the preparation method according to the present invention does not use complex starting materials or protecting groups, and uses only a single step. However, the present invention achieves excellent yields, wherein the formation of byproducts is minimized or avoided.

[0065] Furthermore, the method of the present invention is simple and economical. In particular, the method according to the invention is generally carried out without solvent and / or without any solvent (i.e., as a mass reaction, as a substance reaction, or as a so-called bulk reaction); therefore, the obtained reaction products are not contaminated by solvent, and the solvent does not need to be removed, disposed of, or recycled in an expensive and energy-intensive manner after the method or reaction is carried out. In addition, no toxic byproducts are formed.

[0066] The preparation method according to the invention typically yields a mixture of different 3-hydroxybutyric acid carboxylates, particularly a mixture of carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, i.e., a mixture of at least two different 3-hydroxybutyric acid carboxylates, particularly a mixture of carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol. The resulting crude reaction product or crude mixture can be purified by known methods, particularly by removing any remaining starting compounds and / or any present byproducts. Furthermore, if desired, it can be separated by known methods, particularly by distillation and / or chromatography (e.g., fractionation into individual 3-hydroxybutyric acid carboxylates, i.e., separation of the corresponding monoesters, diesters, etc., or fractionation into fractions with monomer enrichment and depletion portions).

[0067] As previously stated, according to a first aspect, the present invention relates to a method for preparing 3-hydroxybutyric acid carboxylic esters, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylic esters, wherein at least one of the general formulas (I)(CH3-CH(OH)-CH2-C(O)OR 1 (I) 3-hydroxybutyrate, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, reacts with at least one carboxylic acid (II), particularly with at least one carboxylic acid containing one or more carboxyl groups, preferably with at least one carboxylic acid containing two or more carboxyl groups, especially in esterification reactions and / or under esterification conditions, wherein, in general formula (I), group R 1 The expression represents a C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl, thereby obtaining one or more 3-hydroxybutyric acid carboxyl esters, particularly one or more carboxyl esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as reaction product (III).

[0068] According to a specific embodiment of the present invention, compounds of general formula (I) can be used in racemic or enantiomeric (R) form. The (R) configuration refers to the chiral carbon atom at position 3 of the compound of general formula (I).

[0069] According to the present invention, preferably in general formula (I), the group R 1 It represents the ethyl group.

[0070] In other words, according to the present invention, 3-hydroxybutyrate (synonymically also called ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxo-2-butanol) of the formula CH3-CH(OH)-CH2-C(O)OC2H5 is preferably used as the compound of general formula (I).

[0071] This enables particularly efficient process control and high yields while minimizing or suppressing the formation of byproducts. Furthermore, ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxo-2-butanol are readily available commercially, especially as starting compounds for large-scale production, for example, via the Claisen condensation of ethyl acetate.

[0072] According to a specific embodiment of the invention, the carboxylic acid (II) can be used in the form of a free carboxylic acid, a carboxylate, a carboxylic acid ester, or a carboxylic anhydride, particularly in the form of a free carboxylic acid or a carboxylic anhydride.

[0073] According to another specific embodiment of the invention, carboxylic acid (II) may correspond to general formula (IIa).

[0074] (HOOC)mX-(COOH)n(IIa)

[0075] In general formula (IIa),

[0076] ·X represents an organic group, particularly a saturated or unsaturated organic group comprising 1 to 10, preferably 2 to 6, carbon atoms and optionally 1 to 6 oxygen atoms; and

[0077] • The variable m represents an integer between 1 and 3; and

[0078] • The variable n represents the integer 0 or 1;

[0079] In particular, at least one carboxyl group (COOH group), preferably two carboxyl groups (COOH groups), is a terminal and / or a primary carboxyl group (COOH- group).

[0080] In the context, group X may also contain additional carboxyl groups (-COOH), so carboxylic acid (II) may contain up to 7 carboxyl groups in total.

[0081] In this case, it is particularly preferred to use the general formula (IIa).

[0082] • X represents an organic group containing 2 to 6 carbon atoms, which may be saturated or unsaturated and optionally mono- or poly-substituted, particularly substituted with one or more hydroxyl and / or carboxyl groups; and

[0083] • The variable m represents the integer 1; and

[0084] • The variable n represents the integer 0 or 1;

[0085] In particular, at least one carboxyl group (COOH group), preferably both carboxyl groups (COOH groups) are terminal and / or primary carboxyl groups (COOOH groups).

[0086] In particular, the esterification reaction between carboxylic acid (II) and 3-hydroxybutyrate can be carried out particularly efficiently with minimal byproduct formation by using a previously defined carboxylic acid having at least one, preferably two, terminal or primary carboxyl groups, without requiring extreme reaction conditions (e.g., very high temperatures, very high pressures, etc.). Furthermore, the density of the active ingredient (i.e., especially the density of 3-hydroxybutyrate) can be influenced by the number of carboxyl groups present.

[0087] In the method according to the invention, the preferred carboxylic acid (II) is selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid and their anhydrides and combinations or mixtures thereof, particularly selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid and fumaric acid and their anhydrides and combinations or mixtures thereof.

[0088] The aforementioned carboxylic acids are particularly suitable for reaction with 3-hydroxybutyrate esters and are also commercially available.

[0089] In particular, in the method according to the invention, it is preferred that the carboxylic acid (II) is a naturally occurring carboxylic acid or its anhydride or derivative, especially a reaction product, particularly a carboxylic acid or its anhydride or derivative, especially a reaction product occurring in human and / or animal metabolism.

[0090] In particular, it is advantageous in this context to use carboxylic acids or their anhydrides or derivatives that occur in, are produced by, or are associated with the citrate cycle. In this context, for example, a derivative may represent a salt that can be obtained through the oxidation of a metabolite (e.g., from the citrate cycle). By using carboxylic acids or their anhydrides or derivatives that are part of or are reactants, products, or intermediates of human and / or animal metabolism, when using the reaction product according to the invention, an additional energy source (beyond ketone bodies 3-hydroxybutyric acid or 3-hydroxybutyrate) can be provided to the human and / or animal body, and the reaction product is particularly suitable for use as a pharmaceutical, drug, or food.

[0091] Furthermore, in the context of the method according to the invention, it is also preferable that the carboxylic acid (II) is an ingredient approved under food law, particularly an additive.

[0092] Ingredients or additives approved under food law are those permitted to be used in food in certain amounts without posing any health risks. A list of food additives exists throughout the European Union, with each additive having its own label (the so-called E number). For example, the following carboxylic acids are included in the list of food additives: succinic acid (E363), tartaric acid (E334), lactic acid (E270), citric acid (E330), malic acid (E296), adipic acid (E355), and fumaric acid (E297). These acids are all part of the citrate cycle or can be obtained through the oxidation of metabolites of the citrate cycle. The citrate cycle is a biochemical reaction cycle that plays a vital role in the metabolism of aerobic cells in organisms, primarily for the oxidative degradation of organic matter to generate energy and provide intermediates for biosynthesis. Therefore, when using reaction products (III) obtainable from the method according to the invention, the acids formed through degradation can be used by the body as an alternative energy source.

[0093] According to a particular embodiment, this aspect of the invention relates to a method for producing carboxylic acid esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, especially the method described above, wherein at least one of the general formulas (I) (CH3-CH(OH)-CH2-C(O)OR 1 (I) 3-hydroxybutyrate, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, reacts with at least one carboxylic acid (II), particularly in an esterification reaction and / or under esterification conditions, said carboxylic acid (II) being selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid and their anhydrides and combinations or mixtures thereof, particularly selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and their anhydrides and combinations or mixtures thereof, wherein, in general formula (I), the group R 1 The term represents C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl, preferably ethyl, hydroxybutyl or hydroxypentyl, more preferably ethyl, thereby obtaining one or more 3-hydroxybutyric acid carboxyl esters, particularly one or more carboxyl esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as reaction product (III).

[0094] According to another preferred embodiment, this aspect of the invention also relates to a method for producing carboxylic acid esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, especially the method described above, wherein at least one of the general formulas (I) (CH3-CH(OH)-CH2-C(O)OR 1 3-hydroxybutyrate of (I) particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol of general formula (I) reacts with at least one carboxylic acid (II) particularly in an esterification reaction and / or under esterification conditions, said carboxylic acid (II) being selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid and their anhydrides and combinations or mixtures thereof, particularly selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and their anhydrides and combinations or mixtures thereof, wherein in general formula (I), the group R 1 The ethyl group represents the reaction product (III) to obtain one or more 3-hydroxybutyric acid carboxylates, particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0095] According to a specific embodiment of the invention, the reaction can be carried out without solvent and / or without any solvent. This means that the reaction is carried out as a mass reaction, a mass reaction, or a so-called bulk reaction. This has the advantage that the obtained reaction products are not contaminated by the solvent, and that the solvent does not need to be removed, disposed of, or recycled in an expensive and energy-intensive manner after the method or reaction has been carried out. Surprisingly, the method or reaction still proceeds with high conversion and yield, and at least substantially no significant byproducts are formed.

[0096] According to another specific embodiment of the invention, the reaction can be carried out without a catalyst and / or without any catalyst, or alternatively, the reaction can be carried out in the presence of a catalyst, particularly an enzyme and / or a metal-containing and / or metal-based acidic or basic catalyst. In particular, the catalyst can be recycled after the reaction.

[0097] In the method according to the invention, it is particularly preferred that the reaction is carried out in the absence of solvent and / or without any solvent, and in the absence of catalyst and / or without any catalyst.

[0098] Since there are no solvents or catalysts, the reaction products are not contaminated by incompletely removed solvents or catalysts. Furthermore, energy-intensive and costly removal or separation steps are eliminated. Surprisingly, the method according to this preferred embodiment of the invention remains economical and results in high conversion rates without significant byproduct formation.

[0099] As previously described, according to a specific embodiment of the method of the present invention, the reaction can be carried out without a catalyst and / or without any catalyst.

[0100] If the reaction is carried out without a catalyst and / or without any catalyst, it is preferred that the reaction be carried out without a catalyst and / or without any catalyst at a temperature in the range of 20°C to 160°C, particularly in the range of 50°C to 150°C, preferably in the range of 70°C to 140°C, more preferably in the range of 80°C to 135°C, and even more preferably in the range of 100°C to 130°C.

[0101] In the absence of a catalyst, the applied pressure can vary over a wide range. In particular, the reaction can be carried out under pressure without a catalyst and / or without any catalyst, said pressure being in the range of 0.0001 bar to 10 bar, especially in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, and even more preferably about 1 bar.

[0102] When the reaction is carried out in the absence of a catalyst, it is preferable to conduct the reaction in the presence of an inert gas, particularly helium, argon, or nitrogen, with nitrogen being the preferred option. In particular, this helps prevent undesirable side reactions, especially those caused by oxidation or hydrolysis.

[0103] However, as an alternative to this particular implementation, the reaction can also be carried out in the presence of an enzyme as a catalyst.

[0104] In this context, the enzyme may be selected in particular from synthases (ligases), catalases, esterases, lipases, and combinations thereof. According to the invention, synthases (synonymous ligases) are particularly enzymes derived from the class of ligases; ligases are enzymes that catalyze the covalent bonding of two or more molecules. Catalases in the sense of the invention are particularly enzymes capable of converting hydrogen peroxide into oxygen and water. The term esterase specifically refers to enzymes capable of hydrolyzing esters into alcohols and acids (saponification); therefore, these are particularly hydrolytic enzymes, wherein lipolytic esterases are also called lipases. Lipases in the sense of the invention are particularly enzymes capable of separating free fatty acids from lipids (such as glycerides) (lipolysis).

[0105] In this case, the enzyme used as a catalyst may be derived in particular from Candida antarctica, Mucor taeniae (Rhizopus taeniae), Thermophilus sparsely cottony, Candida rubra, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus deltaea, Candida genus and combinations thereof, preferably from Candida antarctica, Mucor taeniae (Rhizopus taeniae) and Thermophilus sparsely cottony.

[0106] According to specific embodiments, the enzyme can be used in an immobilized form, particularly immobilized on a carrier, preferably on a polymer carrier, more preferably on a polymeric organic carrier, even more preferably hydrophobic, and even more preferably immobilized on a carrier based on poly(meth)acrylic acid resin.

[0107] In the context of this invention, it is preferable to recycle the enzyme after the reaction when using an enzyme as a catalyst.

[0108] If the reaction is carried out within the framework of the preparation method of the present invention in the presence of an enzyme as a catalyst, the reaction is preferably carried out at a temperature in the range of 10°C to 80°C, particularly in the range of 20°C to 80°C, preferably in the range of 25°C to 75°C, more preferably in the range of 45°C to 70°C, and even more preferably in the range of 50°C to 70°C.

[0109] When using enzymes as catalysts, the amount of enzyme used can vary over a wide range. Specifically, based on the total amount of starting compounds (I) and (II), the amount of enzyme can range from 0.001 wt% to 20 wt%, particularly from 0.01 wt% to 15 wt%, preferably from 0.1 wt% to 15 wt%, and most preferably from 0.5 wt% to 10 wt%. However, without departing from the scope of the invention, deviations from the above amounts may be necessary in individual cases or for specific applications.

[0110] According to a specific embodiment of the invention, if the reaction is carried out in the presence of an enzyme as a catalyst, the applied pressure range can also vary over a wide range. Typically, the reaction in the presence of the enzyme can be carried out under 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, more preferably in the range of 0.05 bar to 1 bar, and even more preferably about 0.5 bar.

[0111] In a specific embodiment of the reaction according to the invention, carried out in the presence of an enzyme as a catalyst, it is preferred that the reaction be carried out in the presence of an enzyme in the presence of an inert gas, particularly in the presence of helium, argon, or nitrogen, preferably in the presence of nitrogen. As previously described in relation to reactions without a catalyst, the reaction in the presence of an inert gas can prevent undesirable side reactions, particularly those caused by oxidation or hydrolysis.

[0112] According to another alternative embodiment of the invention, the reaction can be carried out, for example, in the presence of a metal-containing and / or metal-based acidic or basic catalyst.

[0113] In this alternative embodiment of the invention, the reaction is carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, the catalyst being particularly selected from: (i) basic catalysts, especially basic or alkaline earth hydroxides and basic or alkaline earth alcohols, such as NaOH, KOH, LiOH, Ca(OH)2, NaOMe, KOMe and sodium tert-butoxide; (ii) acidic catalysts, especially inorganic and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acid; (iii) Lewis acids, especially Lewis acids based on titanium, tin, zinc and aluminum compounds, such as tetrabutyl titanate, stannic acid, zinc acetate, aluminum trichloride and triisopropylaluminum; and (iv) heterogeneous catalysts, especially based on mineral silicates, germanates, carbonates and alumina, such as zeolites, montmorillonite, mordenite, hydrotalcite and alumina, and combinations thereof.

[0114] In this embodiment, Lewis acids based on titanium, tin, zinc, and aluminum compounds, such as tetrabutyl titanate, stannic acid, zinc acetate, aluminum trichloride, and triisopropylaluminum, can be used as catalysts.

[0115] In particular, according to this embodiment, it is preferred to recover the metal-containing and / or metal-based acidic or basic catalyst after the reaction.

[0116] Similarly, in specific embodiments of the reaction according to the invention, carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, the temperature can 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 temperatures ranging from 20°C to 160°C, especially from 50°C to 150°C, preferably from 70°C to 140°C, more preferably from 80°C to 135°C, and even more preferably from 100°C to 130°C.

[0117] Furthermore, according to the same embodiment, the catalyst (i.e., a metal-containing and / or metal-based, acidic or basic catalyst) can also be varied in a wide range of amounts. For example, based on the total amount of starting compounds (I) and (II), the amount of catalyst can range from 0.01 to 30 wt%, particularly from 0.05 to 15 wt%, preferably from 0.1 to 15 wt%, and more preferably from 0.2 to 10 wt%. However, without departing from the scope of the invention, deviations from the above amounts may be made for specific applications or individual cases.

[0118] Furthermore, in this particular embodiment of the invention, where the reaction is carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, the pressure range can also vary over a wide range: in particular, the reaction can be carried out under pressure in the presence of a metal-containing and / or metal-based acidic or basic catalyst, said pressure being 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, more preferably in the range of 0.05 bar to 1 bar, and even more preferably about 1 bar.

[0119] Furthermore, in this particular embodiment of the invention, where the reaction is carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, it is preferable that the reaction is carried out in the presence of an inert gas, particularly in the presence of helium, argon, or nitrogen, preferably in the presence of nitrogen. As previously mentioned, the reaction in the presence of an inert gas prevents undesirable side reactions, particularly those caused by oxidation or hydrolysis.

[0120] This can also vary over a wide range in terms of the total amount of starting materials or starting compounds.

[0121] Considering the economic efficiency of the process and the optimization of the method, especially the minimization of byproducts, it is advantageous that the molar amount of 3-hydroxybutyrate of general formula (I) based on the carboxyl group of carboxylic acid (II) used is in the range of equimolar amount to up to 200 mol% molar excess, particularly in the range of equimolar amount to up to 150 mol% molar excess, preferably in the range of equimolar amount to 100 mol% molar excess.

[0122] Similarly, considering the economics of the process and the optimization of the method, especially with regard to minimizing byproducts, it is advantageous that the molar ratio of 3-hydroxybutyrate of general formula (I) to carboxylic acid (II) is in the range of 1:1 to 10:1, particularly in the range of 2:1 to 8:1, and preferably in the range of 3:1 to 6:1.

[0123] Typically, in the method according to the invention, water is formed simultaneously during the reaction of the 3-hydroxybutyrate of general formula (I) with the carboxylic acid (II) in the form of a free acid. In particular, it is preferred that water be extracted from the reaction, especially continuously, particularly by removal, preferably continuously, especially by distillation or adsorption.

[0124] Typically, in the method according to the invention, during the reaction of the 3-hydroxybutyrate of general formula (I) with a carboxylic acid (II) in the form of anhydride, one mole of the corresponding free carboxylic acid (II) is formed for every mole of anhydride used. In particular, the resulting free carboxylic acid (II) is reacted with the 3-hydroxybutyrate of general formula (I), or, after the reaction, removed and optionally recycled, particularly according to the amount and / or ratio of the starting compounds (I) and (II) used.

[0125] However, when using anhydrides or cyclic anhydrides (such as succinic anhydride or maleic anhydride), the ring is open and no cleavage products are formed; therefore, the reaction products include a terminal free acid. This terminal free acid can then optionally react again with a 3-hydroxybutyrate of general formula (I). The following examples illustrating this method use maleic anhydride in reaction with ethyl 3-hydroxybutyrate:

[0126]

[0127] In the method according to the invention, the composition of the reaction products, particularly the presence of various carboxylic acid esters (III) of 3-hydroxybutyric acid, and their proportions in the mixture, can be controlled and / or adjusted by reaction conditions, particularly by selecting the reaction temperature (conversion temperature) and / or selecting the reaction pressure (conversion pressure) and / or by the absence or provision of a catalyst, and by selecting such catalyst according to type and / or amount and / or by selecting the amount of starting compound (reactant), and / or by providing the removal of any byproducts (particularly water) that may form.

[0128] Therefore, the composition of the product or product mixture can be adjusted according to the application. In particular, for example, the number of substituted 3-hydroxybutyrate groups (3-hydroxybutyrate esters) can be adjusted so that the density of ketone bodies per molecule of 3-hydroxybutyrate ester can be adjusted in a targeted manner.

[0129] After the reaction, the obtained reaction product can be further purified or examined.

[0130] In this context, the obtained reaction products can be fractionated after the reaction has proceeded, particularly by distillation.

[0131] Furthermore, unreacted starting compounds (I) and / or (II) can be separated from the reaction products and subsequently recycled.

[0132] According to a particular embodiment of the preparation method of the present invention, it is particularly possible to carry out the process in such a way that the hydroxyl and / or carboxyl groups still present in the reaction product after the reaction is carried out are at least partially, preferably completely, functionalized, especially esterified.

[0133] In other words, the reaction can result in the partial functionalization of hydroxyl and / or carboxyl groups that still exist, particularly complete functionalization, especially esterification.

[0134] In this particular embodiment of the method according to the invention, the functionalization, particularly esterification, of the remaining hydroxyl and / or carboxyl groups can be achieved by, for example, C2-C... 30 Carboxylic anhydrides of carboxylic acids or C2-C in the case of free hydroxyl groups 30 Fatty acids or C2-C in the case of free carboxyl groups 30 Fatty alcohols undergo the reaction. These can be straight-chain or branched, saturated or mono- or polyunsaturated C2-C. 30 Carboxylic anhydride or C2-C 30 Fatty acids or C2-C 30 - Fatty alcohols. In this case, the remaining hydroxyl groups can react with carboxylic anhydrides or fatty acids, and the remaining carboxyl groups can react with fatty alcohols.

[0135] Within the scope of the method of this invention, as reaction products, one or more 3-hydroxybutyric acid carboxylates of general formula (IIIa) can be obtained and / or can be acquired, particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0136] (R 2 OOC) m -X-(COOR 3 ) n (IIIa)

[0137] In general formula (IIIa),

[0138] ·X represents an organic group, particularly a saturated or unsaturated organic group containing 1 to 10, preferably 2 to 6, carbon atoms and optionally 1 to 6 oxygen atoms;

[0139] • The variable m represents an integer from 1 to 3;

[0140] • The variable n represents the integer 0 or 1; and

[0141] ·R 2 and R 3 Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1 The group R represents C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R is present. 2 and R 3At least one, preferably at least two, of the following groups represent -CH(CH3)-CH2-C(O)OR 1 .

[0142] In particular, group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two in OOC- can be terminal groups and / or primary groups.

[0143] As mentioned above, in this context, group X may also contain other carboxyl groups or be replaced by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0144] In particular, according to the preparation method of the present invention, as reaction product (III), one or more 3-hydroxybutyric acid carboxylates of general formula (IIIa) can be obtained and / or can be obtained, especially one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0145] (R 2 OOC) m -X-(COOR 3 ) n (IIIa)

[0146] In general formula (IIIa),

[0147] ·X indicates saturated or unsaturated and optionally mono- or poly-substituted, particularly by one or more hydroxyl and / or groups -OC(O)-CH2-CH(OH)-CH3 and / or carboxyl and / or groups -C(O)-O-CH(CH3)-CH2-C(O)OR 1 Substituted organic groups containing 2 to 6 carbon atoms;

[0148] • The variable m represents the integer 1;

[0149] • The variable n represents the integer 0 or 1; and

[0150] ·R 2 and R 3 Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1It is a C1-C5 alkyl or hydroxy-C3-C5 alkyl, especially ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R 2 and R 3 At least one, preferably two, of the groups is -CH(CH3)-CH2-C(O)OR 1 .

[0151] In particular, group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two or more in OOC- can be terminal and / or primary groups.

[0152] As mentioned earlier, in the context, group X may also contain other carboxyl groups or be surrounded by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0153] According to a specific embodiment of the method of the present invention, as reaction product (III), one or more 3-hydroxybutyric acid carboxylates of general formula (IIIb) can be obtained and / or can be acquired, particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0154] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0155] In general formula (IIIb),

[0156] ·Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0157] ·Group R 4 Derived from carboxylic acids, said carboxylic acids are selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid, and combinations or mixtures thereof, particularly selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid and fumaric acid, and combinations or mixtures thereof.

[0158] In particular, in the cases of succinic acid, tartaric acid, citric acid, malic acid, adipic acid, fumaric acid, and maleic acid, other carboxyl groups present can be wholly or partially utilized with R as defined above. 1 The group -CH(CH3)-CH2-C(O)OR 1 Esterification.

[0159] In this article, "derived from" refers to the group R 4 Formed from the cited carboxylic acid; in particular, the hydrogen of the carboxyl group is esterified by esterification; that is, in each case, the carboxylic acid ester group of the corresponding acid is used as group R. 4 The presence (i.e., in the case of succinic acid, group R) 4 It is a succinate group; in the case of tartaric acid, it is a tartaric ester group; in the case of lactic acid, it is a lactate group; in the case of citric acid, it is a citrate group; in the case of malic acid, it is a malate group; in the case of adipic acid, it is an adipic ester group; in the case of fumaric acid, it is a fumarate group; and in the case of maleic acid, it is a maleate group.

[0160] According to another specific embodiment of the method of the present invention, as reaction product (III), one or more 3-hydroxybutyric acid carboxylates of general formula (IIIb) can be obtained and / or can be obtained, particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0161] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0162] In general formula (IIIb),

[0163] Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0164] ·Group R 4 Represents one or more of the following groups

[0165]

[0166] Among the above groups, group R 5 Represents hydrogen or having R as defined above 1 The group -CH(CH3)-CH2-C(O)OR 1 .

[0167] According to another specific embodiment of the method of the present invention, as a reaction product, a mixture of at least two different carboxylic acid esters (III), particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, can be obtained, particularly as described above.

[0168] According to a second aspect of the invention, another object is to obtain a (chemical) product or mixture of products by the above method, preferably a 3-hydroxybutyric acid carboxylic acid ester, particularly a carboxylic acid ester of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or a mixture of several 3-hydroxybutyric acid carboxylic acid esters, particularly a mixture of several carboxylic acid esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0169] According to specific embodiments of this aspect, the object of the present invention is a reaction product, particularly a (chemical) product or mixture of products, especially the reaction product as described above.

[0170] The reaction product (III) comprises one or more 3-hydroxybutyric acid carboxylates of general formula (IIIa), particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0171] (R 2 OOC)mX-(COOR 3 )n(IIIa)

[0172] In general formula (IIIa),

[0173] ·X represents an organic group, particularly a saturated or unsaturated organic group containing 1 to 10, preferably 2 to 6, carbon atoms and optionally 1 to 6 oxygen atoms;

[0174] • The variable m represents an integer from 1 to 3;

[0175] • The variable n represents the integer 0 or 1; and

[0176] ·R 2 and R 3 Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1The group R represents C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R is present. 2 and R 3 At least one, preferably at least two, representing groups -CH(CH3)-CH2-C(O)OR 1 ;

[0177] In particular, the group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two in OOC- are terminal and / or primary groups.

[0178] In the context, as previously stated, group X may also contain other carboxyl groups or be surrounded by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0179] According to another specific embodiment of the invention, the reaction product (III) may comprise one or more 3-hydroxybutyric acid carboxylates of general formula (IIIa), particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0180] (R 2 OOC) m -X-(COOR 3 ) n (IIIa)

[0181] In general formula (IIIa),

[0182] ·X indicates saturated or unsaturated and optionally mono- or poly-substituted, particularly by one or more hydroxyl and / or groups -OC(O)-CH2-CH(OH)-CH3 and / or carboxyl and / or groups -C(O)-O-CH(CH3)-CH2-C(O)OR 1 Substituted organic groups containing 2 to 6 carbon atoms;

[0183] • The variable m represents the integer 1;

[0184] • The variable n represents the integer 0 or 1; and

[0185] ·R 2 and R 3Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1 The group R represents C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R is present. 2 and R 3 At least one, preferably at least two, of the groups is -CH(CH3)-CH2-C(O)OR 1 .

[0186] In particular, group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two or more in OOC- can be terminal and / or primary groups.

[0187] In the context, group X may also contain other carboxyl groups or be surrounded by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0188] According to another specific embodiment of the invention, the reaction product (III) may comprise one or more 3-hydroxybutyric acid carboxylates of general formula (IIIb), particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0189] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0190] In general formula (IIIb),

[0191] ·Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0192] ·Group R 4 The derivative is selected from carboxylic acids, which are selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid, and combinations or mixtures thereof, particularly those selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid and fumaric acid, and combinations or mixtures thereof.

[0193] In particular, in the cases of succinic acid, tartaric acid, citric acid, malic acid, adipic acid, fumaric acid, and maleic acid, other carboxyl groups present can be wholly or partially utilized with R as defined above. 1 The group -CH(CH3)-CH2-C(O)OR 1 Esterification.

[0194] As mentioned above, in this context, "derived from" refers to the group R. 4 Formed from the aforementioned carboxylic acids; in particular, the hydrogen atom of the carboxyl group is esterified; that is, in each case, the carboxylic acid ester group of the corresponding acid is used as group R. 4 The presence (i.e., in the case of succinic acid, group R) 4 It is a succinate group; in the case of tartaric acid, it is a tartaric ester group; in the case of lactic acid, it is a lactate group; in the case of citric acid, it is a citrate group; in the case of malic acid, it is a malate group; in the case of adipic acid, it is an adipic ester group; in the case of fumaric acid, it is a fumarate group; and in the case of maleic acid, it is a maleate group.

[0195] According to another specific embodiment of the invention, the reaction product (III) may comprise one or more 3-hydroxybutyric acid carboxylates of general formula (IIIb), particularly one or more carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0196] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0197] In general formula (IIIb),

[0198] ·Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0199] ·Group R 4 Represents one or more of the following groups

[0200]

[0201]

[0202] Among the above groups, R 5 Represents hydrogen or R as defined above 1 The group -CH(CH3)-CH2-C(O)OR1 .

[0203] According to a particular embodiment, the reaction product may comprise a mixture of at least two different carboxylic acid esters, particularly 3-hydroxybutyric acid carboxyl ester (III) as defined above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0204] Therefore, the object of the present invention is also the 3-hydroxybutyric acid carboxylic acid ester (= 4-oxo-2-butanol carboxylic acid ester) of general formula (IIIa), especially the carboxylic acid esters of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0205] (R 2 OOC) m -X-(COOR 3 ) n (IIIa)

[0206] In general formula (IIIa),

[0207] ·X represents an organic group, particularly a saturated or unsaturated organic group containing 1 to 10, preferably 2 to 6, carbon atoms and optionally 1 to 6 oxygen atoms;

[0208] • The variable m represents an integer from 1 to 3;

[0209] • The variable n represents the integer 0 or 1; and

[0210] ·R 2 and R 3 Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1 The group R represents C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R is present. 2 and R 3 At least one, preferably at least two, representing groups -CH(CH3)-CH2-C(O)OR 1 .

[0211] In particular, group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two in OOC- can be terminal groups and / or primary groups.

[0212] As mentioned above, group X may also contain other carboxyl groups or be surrounded by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0213] According to specific embodiments, 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, may correspond to general formula (IIIa).

[0214] (R 2 OOC) m -X-(COOR 3 ) n (IIIa)

[0215] In general formula (IIIa),

[0216] ·X indicates saturated or unsaturated and optionally mono- or poly-substituted, particularly by one or more hydroxyl and / or groups -OC(O)-CH2-CH(OH)-CH3 and / or carboxyl and / or groups -C(O)-O-CH(CH3)-CH2-C(O)OR 1 Substituted organic groups containing 2 to 6 carbon atoms;

[0217] • The variable m represents the integer 1;

[0218] • The variable n represents the integer 0 or 1; and

[0219] ·R 2 and R 3 Each independently represents hydrogen or a group -CH(CH3)-CH2-C(O)OR 1 In which the group R 1 The group R represents C1-C5 alkyl or hydroxy-C3-C5 alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, provided that the group R is present. 2 and R 3 At least one, preferably at least two, of the groups is -CH(CH3)-CH2-C(O)OR 1 .

[0220] In particular, group R 2 OOC- and / or R 3 At least one of OOC-, preferably the group R 2 OOC- and R 3 The two or more in OOC- can be terminal and / or primary groups.

[0221] Group X may also contain other carboxyl groups or be replaced by -CH(CH3)-CH2-C(O)OR 1 Substituted carboxyl group (i.e., the group -COO-CH(CH3)-CH2-C(O)OR) 1 ).

[0222] According to another specific embodiment, 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, may correspond to general formula (IIIb).

[0223] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0224] In general formula (IIIb),

[0225] ·Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0226] ·Group R 4 Derived from carboxylic acids, said carboxylic acids are selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid and maleic acid, and combinations or mixtures thereof, particularly selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid and fumaric acid, and combinations or mixtures thereof.

[0227] In particular, in the cases of succinic acid, tartaric acid, citric acid, malic acid, adipic acid, fumaric acid, and maleic acid, other carboxyl groups present can be completely or partially replaced by R as defined above. 1 The group -CH(CH3)-CH2-C(O)OR 1 Esterification.

[0228] As mentioned above, "derived from" refers to the group R 4 Formed from the aforementioned carboxylic acids; in particular, the hydrogen atom of the carboxyl group is esterified; that is, in each case, the carboxylic acid ester group of the corresponding acid is used as group R. 4 The presence (i.e., in the case of succinic acid, group R) 4It is a succinate group. In the case of tartaric acid, it is a tartaric ester group; in the case of lactic acid, it is a lactate group; in the case of citric acid, it is a citrate group; in the case of malic acid, it is a malate group; in the case of adipic acid, it is an adipic ester group; in the case of fumaric acid, it is a fumarate group; and in the case of maleic acid, it is a maleate group.

[0229] According to a preferred embodiment of the invention, 3-hydroxybutyric acid carboxylates, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol carboxylates, can correspond to general formula (IIIb).

[0230] CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb)

[0231] In general formula (IIIb),

[0232] ·Group R 1 This refers to C1-C5 alkyl or hydroxy-C3-C5-alkyl, particularly ethyl, butyl, pentyl, hydroxybutyl, or hydroxypentyl, preferably ethyl, hydroxybutyl, or hydroxypentyl, more preferably ethyl, and

[0233] ·Group R 4 Represents one or more of the following groups

[0234]

[0235]

[0236] Among the above groups, group R 5 Represents hydrogen or having R as defined above 1 The group -CH(CH3)-CH2-C(O)OR 1 .

[0237] Furthermore, according to a particular embodiment, another object of the present invention is a mixture comprising at least two different carboxylates, particularly 3-hydroxybutyric acid carboxylates (III) as described above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol.

[0238] The reaction products obtained according to the method of the present invention or the reaction products of the present invention as defined above, and / or the carboxylic esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as defined above, or the carboxylic esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as defined above, and / or mixtures obtainable according to the preparation method of the present invention or mixtures of the present invention as defined above, include many advantages and special features compared to the prior art:

[0239] If the applicant has inadvertently discovered that the reaction products obtained according to the method of the present invention or the reaction products of the present invention as defined above and / or the carboxylic acid esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or the carboxylic acid esters of the present invention as defined above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, and / or mixtures obtained according to the preparation method of the present invention or mixtures of the present invention as defined above, are suitable as precursors or metabolites of 3-hydroxybutyric acid or its salts because, on the one hand, it is physiologically, particularly in the gastrointestinal tract, converted to 3-hydroxybutyric acid or its salts, and on the other hand, particularly with regard to non-toxic and acceptable sensory properties, it simultaneously possesses good physiological compatibility or tolerability.

[0240] Furthermore, reaction products obtainable according to the method of the present invention or reaction products of the present invention as defined above, and / or 3-hydroxybutyric acid carboxylates, particularly carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or 3-hydroxybutyric acid carboxylates of the present invention as defined above, particularly carboxylates of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, and / or mixtures obtainable according to the method of the present invention or mixtures of the present invention as defined above, are readily available or commercially usable on a synthetic basis, and possess the desired pharmaceutical or pharmacological quality.

[0241] Furthermore, reaction products obtainable according to the method of the present invention or reaction products of the present invention as defined above, and / or carboxylic esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or carboxylic esters of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as defined above, and / or mixtures obtainable according to the preparation method of the present invention or mixtures of the present invention as defined above, may be provided, if desired, in enantiomeric pure or enantiomeric enriched form.

[0242] The reaction products obtainable according to the method of the present invention or the reaction products of the present invention as defined above, and / or the carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or the carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, as defined above, and / or mixtures obtainable according to the method of the present invention or mixtures of the present invention as defined above, thus represent effective pharmacological drug targets in the context of ketone body therapy in humans or animals.

[0243] The remaining aspects of the invention will be explained in more detail below.

[0244] According to a third aspect of the invention, another subject of the invention is a pharmaceutical composition, particularly a drug or pharmaceutical agent, comprising: a reaction product obtainable according to the preparation method of the invention or the reaction product of the invention as defined above, and / or a carboxylic acid ester of 3-hydroxybutyric acid, particularly a carboxylic acid ester of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or a carboxylic acid ester of 3-hydroxybutyric acid, particularly a carboxylic acid ester of 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol as defined above, and / or a mixture obtainable according to the preparation method of the invention or a mixture of the invention as defined above.

[0245] In particular, according to this aspect of the invention, the present invention relates to pharmaceutical compositions for the prevention and / or therapeutic treatment of diseases in humans or animals. This may particularly relate to diseases associated with disorders 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 defects (GLUT1 deficiency), VL-FAOD, and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and uric acid arthritis, gastrointestinal diseases such as chronic inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipid disease, particularly Niemann-Pick disease, diabetes, and the effects or side effects of chemotherapy.

[0246] Similarly, according to a fourth aspect of the invention, another subject of the invention is a reaction product obtainable according to the method of preparation of the invention or the reaction product of the invention as defined above, and / or a carboxylic acid ester of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or a carboxylic acid ester of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol as defined above, and / or a mixture obtainable according to the method of preparation of the invention or a mixture of the invention as defined above, for preventive and / or therapeutic treatment or for the prevention and / or therapeutic treatment of human... Diseases of the human or animal body, particularly those related to disorders 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 defects (GLUT1 deficiency), VL-FAOD, and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and uric acid arthritis, gastrointestinal diseases such as chronic inflammatory bowel disease, especially ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipid disease, especially Niemann-Pick disease, diabetes, and the effects or side effects of chemotherapy.

[0247] Similarly, according to a fifth aspect of the invention, another subject of the invention is the use of reaction products obtainable according to the method of preparation of the invention or the reaction products of the invention as defined above, and / or carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or carboxylates of 3-hydroxybutyric acid as defined above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, and / or mixtures obtainable according to the method of preparation of the invention or mixtures of the invention as defined above, for preventive and / or therapeutic treatment or for the production of medicaments for preventive and / or therapeutic purposes. / or therapeutic treatment for diseases in humans or animals, particularly those related to disorders 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 defects (GLUT1 deficiency), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and uric acid arthritis, gastrointestinal diseases such as chronic inflammatory bowel disease, especially ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipid disease, especially Niemann-Pick disease, diabetes and the effects or side effects of chemotherapy.

[0248] Similarly, according to a sixth aspect of the invention, another subject of the invention is the use of reaction products obtainable according to the method of preparation according to the invention or the reaction products of the invention as defined above, and / or carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or carboxylates of 3-hydroxybutyric acid as defined above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, and / or mixtures obtainable according to the method of preparation according to the invention or mixtures of the invention as defined above, for preventive and / or therapeutic treatment or for the production of pharmaceutical agents for preventive and / or therapeutic treatment or for catabolic states such as starvation, dieting, or low-carbohydrate nutrition.

[0249] Similarly, according to the seventh aspect of the invention, another subject of the invention is food and / or food products comprising reaction products obtainable according to the preparation method of the invention or the reaction products of the invention as defined above, and / or carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol as defined above, and / or mixtures obtainable according to the preparation method of the invention or mixtures of the invention as defined above.

[0250] According to a particular implementation, food and / or food products can be essentially dietary supplements, functional foods, novel foods, food additives, food supplements, dietary foods, energy snacks, appetite suppressants, or strength and / or endurance sports supplements.

[0251] Finally, according to an eighth aspect of the invention, another subject of the invention is the use in food and / or food products of reaction products obtainable according to the method of the invention and / or carboxylates of 3-hydroxybutyric acid, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, or carboxylates of 3-hydroxybutyric acid as defined above, particularly 4-oxo-4-(C1-C5-alkoxy)-2-butanol or 4-oxo-4-(hydroxy-C3-C5-alkoxy)-2-butanol, and / or mixtures obtainable according to the method of the invention.

[0252] According to this aspect of the invention, food and / or food products can essentially be dietary supplements, functional foods, novel foods, food additives, food supplements, dietary foods, energy snacks, appetite suppressants, or strength and / or endurance sports supplements.

[0253] Those skilled in the art will readily recognize or implement other embodiments, modifications, and variations of the present invention upon reading the specification, without departing from the scope of the present invention.

[0254] The present invention is illustrated by the following embodiments; however, these embodiments are not intended to limit the invention in any way, but are merely intended to explain exemplary and non-limiting implementations and configurations of the invention. These examples are further described with reference to the following description of the drawings and the drawings themselves. In this context, all features described and / or illustrated, individually or in any combination, constitute the subject matter of the invention, regardless of their summary in the claims and their reverse reference. Attached Figure Description

[0255] It shows:

[0256] Figure 1 : Schematic diagram of the conversion time process of the reaction between succinic anhydride and 3-hydroxybutyric acid.

[0257] Figure 2 : Schematic diagram of the conversion time process of the reaction between citric acid and 3-hydroxybutyric acid.

[0258] Figure 3 : Schematic diagram of the conversion time process of the reaction between malic acid and 3-hydroxybutyric acid.

[0259] Figure 1 The conversion time of the reaction between succinic anhydride and ethyl 3-hydroxybutyrate is shown, with the X-axis representing the reaction time in hours [h] and the Y-axis representing the GC area analysis in percentage [%). The process or amounts of the starting compound ethyl 3-hydroxybutyrate (3-BHB-EE) and the reaction products ethyl 3-hydroxybutyrate monosuccinate (BS-BHB-EE) and ethyl 3-hydroxybutyrate diester (BS-(BHB-EE)2) are shown. Furthermore, the time of addition of titanium (IV) catalyst and the time of addition of molecular sieve for adsorption and removal of water are labeled, respectively.

[0260] Throughout the reaction time, ethyl 3-hydroxybutyrate was converted. After 10 hours of reaction, the conversion of succinic anhydride to succinic acid monoester of ethyl 3-hydroxybutyrate in the first reaction step was complete. The addition of catalyst did not significantly increase the conversion rate. Further catalyst addition led to an increase in the formation of ethyl 3-hydroxybutyrate succinate diester, although the amount of ethyl 3-hydroxybutyrate monoester formed was slightly reduced due to further conversion to ethyl 3-hydroxybutyrate succinate diester. The addition of molecular sieves did not significantly increase the conversion rate. After 30 hours of reaction, approximately equal amounts of ethyl 3-hydroxybutyrate monoester and succinate diester were present.

[0261] Figure 2 The conversion time of the reaction between citric acid and ethyl 3-hydroxybutyrate is shown, with the X-axis representing the conversion time in hours [h] and the Y-axis representing the GC area analysis in percentage [%). The process or amounts of the starting compound ethyl 3-hydroxybutyrate (3-BHB-EE) and citric acid, as well as the reaction products ethyl 3-hydroxybutyrate citrate monoester (CS-BHB-EE), ethyl 3-hydroxybutyrate citrate diester (CS-(BHB-EE)2), and ethyl 3-hydroxybutyrate citrate triester (CS-(BHB-EE)3) are shown. Furthermore, the time of addition of the titanium (IV) catalyst is labeled.

[0262] Throughout the reaction time, ethyl 3-hydroxybutyrate is converted. At the start of the reaction, significant formation of ethyl 3-hydroxybutyrate mono- and citrate diesters occurs. After approximately 13 hours of reaction time, the amount of ethyl 3-hydroxybutyrate mono- and citrate diesters decreases again because more ethyl 3-hydroxybutyrate mono- and citrate diesters are converted compared to the formation of new ethyl 3-hydroxybutyrate mono- and citrate diesters. After approximately 21 hours of reaction time, citric acid is completely reacted, and therefore, from this point onward, no new ethyl 3-hydroxybutyrate mono- and citrate diesters are formed. The first addition of titanium (IV) catalyst slightly improves the conversion of ethyl 3-hydroxybutyrate mono- and citrate diesters, but a second addition does not result in a significant further increase in conversion.

[0263] Figure 3 The conversion time of the reaction between malic acid and ethyl 3-hydroxybutyrate is shown, with the X-axis representing the conversion time in hours [h] and the Y-axis representing the GC area analysis in percentage [%). The process or amounts of the starting compound ethyl 3-hydroxybutyrate (3-BHB-EE) and malic acid, as well as the reaction products ethyl 3-hydroxybutyrate malate monoester (malic acid BHB-EE monoester) and ethyl 3-hydroxybutyrate malate diester (malic acid BHB-EE diester), are shown. Furthermore, the time of addition of the titanium (IV) catalyst is labeled separately.

[0264] Ethyl 3-hydroxybutyrate was converted throughout the reaction time. After a reaction time of 25 hours, the conversion of malic acid to the malic acid monoester of ethyl 3-hydroxybutyrate in the first reaction step was complete. Each addition of catalyst did not result in any significant increase in conversion. Detailed Implementation

[0265] Example:

[0266] Abbreviations used

[0267] ·3-BHB-EE=BHB-EE: ethyl 3-hydroxybutyrate (= ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol)

[0268] ·3-BHB=BHB:3-hydroxybutyric acid

[0269] ·BS: Succinic acid

[0270] ·CS: Citric acid

[0271] I. Production Examples of Specific Embodiments of the Method According to the Invention Without the Use of a Catalyst

[0272] I.1. Preparation of ethyl 3-hydroxybutyrate tartrate

[0273] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 38 g of tartaric acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0274] A mixture of ethyl 3-hydroxybutyric acid tartrate monoester [= mono-(4-ethoxy-4-oxo-but-2-yl) tartrate or tartrate mono-(4-ethoxy-4-oxo-but-2-yl) ester] and ethyl 3-hydroxybutyric acid tartrate diester [= di-(4-ethoxy-4-oxo-but-2-yl)-tartrate or tartrate di-(-4-ethoxy-4-oxo-but-2-yl)-ester] was obtained.

[0275] Ethyl 3-hydroxybutyric acid tartrate monoester can also be synonymously called 4[(4-ethoxy-4-oxobut-2-yl)-oxo]-2,3-dihydroxy-4-oxobutyric acid, while ethyl 3-hydroxybutyric acid tartrate diester can also be synonymously called 1,4-di-(4-ethoxy-4-oxobut-2-yl)-2,3-hydroxybutadiene ester or di-(4-ethoxy-4-oxobut-2-yl)-2,3-hydroxysuccinate.

[0276] Mass spectrometry (MS), gel permeation chromatography (GPC), and proton resonance spectroscopy were used to analyze the spectrometers. 1 Characterized by H-NMR.

[0277] The reaction process is illustrated below:

[0278]

[0279] Preparation of 1.2. Ethyl 3-hydroxybutyrate lactate

[0280] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 57 g of lactic acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting reaction water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0281] Ethyl 3-hydroxybutyrate lactate monoester [= mono-(4-ethoxy-4-oxo-but-2-yl)-lactic acid ester or lactate mono-(-4-ethoxy-4-oxo-but-2-yl) ester] was obtained by means of MS, GPC and... 1 Characterized by H-NMR.

[0282] The reaction process is illustrated below:

[0283]

[0284] Preparation of I.3. Ethyl 3-hydroxybutyrate succinate

[0285] Alternative Option 1: Use succinic anhydride

[0286] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 24 g of succinic anhydride were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Excess ethyl 3-hydroxybutyrate was then distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0287] A mixture of ethyl 3-hydroxybutyric acid succinate monoester [= mono-(4-ethoxy-4-oxo-but-2-yl)-succinate or succinate mono-(4-ethoxy-4-oxo-but-2-yl) ester] and ethyl 3-hydroxybutyric acid succinate diester [= di-(4-ethoxy-4-oxo-but-2-yl)-succinate or succinate di-(4-ethoxy-4-oxo-but-2-yl) ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0288] Ethyl 3-hydroxybutyric acid succinate monoester can also be synonymously called 4-[(4-ethoxy-4-oxobut-2-yl)-oxo]-4-oxobutyric acid, while the succinate diester of ethyl 3-hydroxybutyric acid can also be synonymously called 1,4-di-(4-ethoxy-4-oxobut-2-yl)-succinate or di-(4-ethoxy-4-oxobut-2-yl)-succinate.

[0289] The reaction process is illustrated below:

[0290]

[0291] Alternative Option 2: Use free succinic acid

[0292] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 33 g of succinic acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0293] A mixture of ethyl 3-hydroxybutyric acid monosuccinate [= mono-(4-ethoxy-4-oxo-but-2-yl)-succinate or mono-(4-ethoxy-4-oxo-but-2-yl)-succinate] and ethyl 3-hydroxybutyric acid diester [= di-(4-ethoxy-4-oxo-but-2-yl)-succinate or di-(4-ethoxy-4-oxo-but-2-yl)-succinate] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0294] Ethyl 3-hydroxybutyric acid succinate monoester can also be synonymously called 4-[(4-ethoxy-4-oxobut-2-yl)-oxo]-4-oxobutyric acid, while the succinate diester of ethyl 3-hydroxybutyric acid can also be synonymously called 1,4-di-(4-ethoxy-4-oxobut-2-yl)-succinate or di-(4-ethoxy-4-oxobut-2-yl)-succinate.

[0295] The reaction process is illustrated below:

[0296]

[0297] Preparation of I.4. Ethyl 3-hydroxybutyrate citrate

[0298] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 32 g of citric acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0299] A mixture of mono- and mono-citrate esters of ethyl-3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-citrate or mono-(4-ethoxy-4-oxo-but-2-yl)-citrate], die- and die- and tri-citrate esters of ethyl-3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-citrate or di-(4-ethoxy-4-oxo-but-2-yl)-citrate], and tri- and tri-citrate esters of ethyl-3-hydroxybutyric acid [= tri-(4-ethoxy-4-oxo-but-2-yl)-citrate or tri-(4-ethoxy-4-oxo-but-2-yl)-citrate]. Analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0300] The citrate monoester of ethyl 3-hydroxybutyric acid can also be synonymously called 2-{2-[(4-ethoxy-4-oxobut-2-yl)-oxy]-2-oxoethyl}-2-hydroxybutyric acid, or 2-{2-[(4-ethoxy-4-oxobut-2-yl)-oxy]-2-oxoethyl}-2-hydroxysuccinic acid, while the citrate diester of ethyl 3-hydroxybutyric acid can also be synonymously called 4-[(4-ethoxy-4-oxobut-2-yl)-oxy]-2-{2[(4-ethoxy-4-oxobut-2-yl)-oxy]-2-oxoethyl}-2-hydroxy-4-oxobutyric acid, and the citrate triester of ethyl 3-hydroxybutyric acid can also be synonymously called 1,2,3-tris-(4-ethoxy-4-oxobut-2-yl)-2-hydroxypropane-1,2,3-tricarboxylic acid ester.

[0301] The reaction process is illustrated below:

[0302]

[0303] Preparation of maleate ester of 1,5-ethyl-3-hydroxybutyric acid

[0304] Alternative Option 1: Use maleic anhydride

[0305] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 29 g of maleic anhydride were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0306] A mixture of maleic acid monoesters of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid mono-(4-ethoxy-4-oxo-but-2-yl)-ester] and maleic acid diesters of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid di-(4-ethoxy-4-oxo-but-2-yl)-ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0307] The reaction process is illustrated below:

[0308]

[0309] Alternative Option 2: Use free maleic acid

[0310] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 33 g of maleic acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0311] A mixture of maleic acid monoesters of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid mono(4-ethoxy-4-oxo-but-2-yl)-ester] and maleic acid diesters of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid di-(4-ethoxy-4-oxo-but-2-yl)-ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0312] The reaction process is illustrated below:

[0313]

[0314] Preparation of I.6. Ethyl 3-hydroxybutyrate fumarate

[0315] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 33 g of fumaric acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0316] A mixture of fumarate monoester of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-fumarate or fumarate mono-(4-ethoxy-4-oxo-but-2-yl) ester] and fumarate diester of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)fumarate or fumarate di-(4-ethoxy-4-oxo-but-2-yl) ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0317] The reaction process is illustrated below:

[0318]

[0319] Preparation of malate of 1.7. Ethyl 3-hydroxybutyric acid

[0320] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 33 g of malic acid (2-hydroxysuccinic acid) were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, with the resulting water continuously separated. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0321] A mixture of a mono- and a diester of ethyl 3-hydroxybutyric acid malate [= mono-(4-ethoxy-4-oxo-but-2-yl)-malate or mono-(4-ethoxy-4-oxo-but-2-yl)-malate] and a di- and di-(4-ethoxy-4-oxo-but-2-yl)-malate were obtained. The malate was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0322] The malic acid monoester of ethyl 3-hydroxybutyric acid can also be synonymously called 4-[(4-ethoxy-4-oxo-but-2-yl)-oxo]-2-hydroxy-4-oxobutyric acid, while the malic acid diester of ethyl 3-hydroxybutyric acid can also be synonymously called 1,4-di-(4-ethoxy-4-oxobut-2-yl)-2-hydroxysuccinate or bis(4-ethoxy-4-oxobut-2-yl)-2-hydroxysuccinate.

[0323] The reaction process is illustrated below:

[0324]

[0325] I.8. ​​Preparation of Ethyl 3-hydroxybutyrate adipate

[0326] In a 500 mL multi-necked flask equipped with a fractionating distiller (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 37 g of adipic acid were provided. The reaction mixture was stirred at 120 °C and N2 for 7 hours, and the resulting water was continuously removed by distillation. Subsequently, excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was vaporized under high vacuum for 2–4 hours.

[0327] A mixture of adipic acid monoester of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-adipate or adipic acid mono-(-4-ethoxy-4-oxo-but-2-yl) ester] and adipic acid diester of ethyl 3-hydroxybutyric acid [= di-(-4-ethoxy-4-oxo-but-2-yl)-adipate or adipic acid di-(4-ethoxy-4-oxo-but-2-yl) ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0328] The reaction process is illustrated below:

[0329]

[0330] Preparation of more carboxylic esters of ethyl 3-hydroxybutyric acid.

[0331] In addition, the above synthesis I.1, I.2, I.4 and I.6 to I.8 were repeated respectively, using the corresponding carboxylic anhydride instead of the free carboxylic acid (i.e., in the case of Example I.1, tartaric anhydride was used instead of tartaric acid, in the case of Example I.2, lactic anhydride was used instead of lactic acid, in the case of Example I.4, citric anhydride was used instead of citric acid, in the case of Example I.6, fumaric anhydride was used instead of fumaric acid, in the case of Example I.7, malic anhydride was used instead of malic acid, and in the case of Example I.8, adipic anhydride was used instead of adipic acid).

[0332] Similar results were obtained. In this context, the corresponding carboxylic acid formed is not continuously removed during the reaction, but can continue to react with ethyl 3-hydroxybutyrate. After the reaction is complete, excess ethyl 3-hydroxybutyrate, excess carboxylic anhydride, or free carboxylic acid is removed by distillation (depending on the molar ratio of the reactants used).

[0333] Furthermore, Examples I.1 to I.8 mentioned above are repeated, however, with the use of other 3-hydroxybutyrate esters (i.e., ethyl 3-hydroxybutyrate is replaced by 3-hydroxybutyrate (hydroxybutyl) ester or 3-hydroxybutyrate (hydroxypentyl) ester, respectively). 3-hydroxybutyrate (hydroxybutyl) ester is obtained by esterification of 3-hydroxybutyrate with butanediol (e.g., with 1,3-butanediol), while 3-hydroxybutyrate (hydroxypentyl) ester is obtained by esterification of 3-hydroxybutyrate with pentanediol (e.g., with 1,3-pentanediol).

[0334] In the first series, free carboxylic acids are used as reactants, while in the second series, the corresponding carboxylic anhydrides are used.

[0335] Similar results were obtained. Purification and separation were performed in the same manner.

[0336] However, the above examples were repeated using methyl and ethyl esters of carboxylic acids. Similar results were obtained. Purification and separation were performed in the same manner.

[0337] II. Preparation Examples of Alternative Specific Embodiments of the Method According to the Invention Using a Metal Catalyst

[0338] All the chemical synthesis examples described in Part I were repeated, however, with the addition of 1.6 g of tetrabutyl titanate (titanium(IV)-catalyst). The titanium(IV) catalyst was provided in a flask along with the other reactants. The reaction proceeded accordingly to the examples described above. Similar results were obtained. The catalyst was separated and recycled after the reaction.

[0339] III. Preparation Examples of Another Alternative Specific Embodiment of the Method According to the Invention Using an Enzyme Catalyst

[0340] All the chemical synthesis examples described in Part I were repeated, however, with an enzyme added as a catalyst. Similar results were obtained. The catalyst (i.e., the enzyme) was separated and recycled after the reaction was complete.

[0341] Some of the embodiments that were performed are selected and described below. All other previously mentioned synthetic embodiments were performed in a similar manner and provided similar results.

[0342] III.1. Production of Ethyl 3-hydroxybutyrate tartrate

[0343] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 38 g of tartaric acid, and 1.7 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. 435 or from Strem Chemicals, Inc. 435). The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0344] A mixture of mono- and di-(4-ethoxy-4-oxo-but-2-yl)-tartrate esters of ethyl 3-hydroxybutyric acid was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0345] III.2. Production of Ethyl 3-hydroxybutyrate lactate

[0346] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 57 g of lactic acid, and 1.8 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0347] Obtain the lactic acid monoester of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-lactic acid ester or lactic acid mono-(4-ethoxy-4-oxo-but-2-yl) ester]. This was achieved by MS, GPC, and... 1 Characterized by H-NMR.

[0348] III. Production of ethyl 3-hydroxybutyrate succinate

[0349] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 33 g of succinic acid, and 1.6 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0350] A mixture of ethyl 3-hydroxybutyric acid monosuccinate [= mono-(4-ethoxy-4-oxo-but-2-yl)-succinic acid or succinate mono-(-4-ethoxy-4-oxo-but-2-yl) ester] and ethyl 3-hydroxybutyric acid diester [= bis-(4-methoxy-4-oxo-but-2-yl)-succinate or succinate di-(4-ethoxy-4-oxo-but-2-yl)-ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0351] III.4. Preparation of Ethyl 3-hydroxybutyrate citrate

[0352] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 32 g of citric acid, and 1.8 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0353] A mixture of mono- and di-citrate esters of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-citrate or mono-(4-ethoxy-4-oxo-but-2-yl)-citrate], di- and di-citrate esters of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-citrate or di-(4-ethoxy-4-oxo-but-2-yl)-citrate], and tri- and tri-citrate esters of ethyl 3-hydroxybutyric acid [= tri-(4-ethoxy-4-oxo-but-2-yl)-citrate or tri-(4-ethoxy-4-oxo-but-2-yl)-citrate] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0354] III.5. Preparation of maleate ester of ethyl 3-hydroxybutyric acid

[0355] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 33 g of maleic acid, and 1.6 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0356] A mixture of maleic acid monoesters of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid mono-(4-ethoxy-4-oxo-but-2-yl)-ester] and maleic acid diesters of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-maleate or maleic acid di-(4-ethoxy-4-oxo-but-2-yl)-ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0357] III.6. Preparation of malate ester of ethyl 3-hydroxybutyric acid

[0358] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic), 33 g of malic acid (2-hydroxysuccinic acid), and 1.6 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0359] A mixture of a mono- and a diester of ethyl 3-hydroxybutyric acid malate [= mono-(4-ethoxy-4-oxo-but-2-yl)-malate or mono-(4-ethoxy-4-oxo-but-2-yl)-malate] and a di- and di-(4-ethoxy-4-oxo-but-2-yl)-malate were obtained. The malate was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0360] III.7. Preparation of Ethyl 3-hydroxybutyrate adipate

[0361] In a 500 mL multi-necked flask equipped with a fractionating distillation unit (partial condenser) and a distillation bridge, 132 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 37 g of adipic acid and 1.7 g of immobilized enzyme (CALB lipase on a polymer carrier, derived from Candida antarctica, such as from Sigma-Aldrich or Merck) are provided. Or from Strem Chemicals, Inc. The reaction mixture was stirred at 70°C and under vacuum (<500 mbar) for 7 hours. The enzyme was then filtered out, and excess ethyl 3-hydroxybutyrate was distilled off under vacuum. The resulting residue was steam-treated under high vacuum for 2–4 hours.

[0362] A mixture of adipic acid monoester of ethyl 3-hydroxybutyric acid [= mono-(4-ethoxy-4-oxo-but-2-yl)-adipate or adipic acid mono-(4-ethoxy-4-oxo-but-2-yl) ester] and adipic acid diester of ethyl 3-hydroxybutyric acid [= di-(4-ethoxy-4-oxo-but-2-yl)-adipate or adipic acid di-(4-ethoxy-4-oxo-but-2-yl) ester] was obtained. The mixture was analyzed by MS, GPC, and... 1 Characterized by H-NMR.

[0363] III.8. Preparation of other carboxylic acid esters of ethyl-3-hydroxybutyric acid

[0364] Furthermore, the above preparation examples were repeated, however, using other 3-hydroxybutyrate esters (i.e., ethyl 3-hydroxybutyrate was replaced with 3-hydroxybutyrate (hydroxybutyl) ester and 3-hydroxybutyrate (hydroxypentyl) ester, respectively). Similar results were obtained. Purification and separation were performed in the same manner.

[0365] Similarly, the preparation examples described above were repeated, however, using methyl and ethyl esters of carboxylic acids. Similar results were obtained. Purification and separation were performed in the same manner.

[0366] IV. Dynamics and Structural Analysis

[0367] Furthermore, the kinetics of the method of the present invention were analyzed. To this end, the conversion time of the reactions of succinic anhydride with ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate), citric acid with ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate), and malic acid with ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate) were determined.

[0368] IV.1. Reaction of succinic anhydride with ethyl 3-hydroxybutyrate

[0369] In a 500 mL multi-necked flask equipped with a fractionating distillation apparatus (partial condenser) and a distillation bridge, 525 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 133 g of succinic anhydride were reacted at 130 °C and 70 mbar for 13 h. The mixture was then divided into two halves.

[0370] For the first half, three drops of tetrabutyl titanate (titanium(IV)-catalyst) at 100°C were added to the reaction mixture, and the reaction was stirred at 130°C for another 17 hours, gradually reducing the pressure to 40 mbar. After 7 hours of reaction, fresh tetrabutyl titanate was added, and after another 6 hours, 22 g of molecular sieve (Molsieve) was added. To remove the reaction water. After the reaction time is complete, filter the reaction mixture.

[0371] Throughout the reaction time, samples were periodically taken and their composition analyzed. The resulting conversion time process is as follows: Figure 1 As shown.

[0372] The conversion time process shows that after 10 hours of reaction time, the conversion of succinic anhydride to BS-E-BHB monoester (succinic acid monoester of ethyl 3-hydroxybutyric acid) in the first reaction step was completed. The addition of a catalyst did not lead to a significant increase in the conversion rate.

[0373] The mixture was purified in the second half for further analysis. First, excess 3BHB-EE was removed, and the residue was purified by column chromatography. To identify the structure of the succinate of ethyl 3-hydroxybutyric acid, the individual esters were purified and separated by column chromatography (i.e., separation of monoesters and diesters). For this purpose, excess 3-BHB-EE was removed, and the product mixture was then column-pressed on silica gel. An ethyl acetate / cyclohexane mixture with 0.5% triethylamine in a 2 / 1 ratio was used as the running medium. Subsequently, the two fractions A and B, as well as the unfractionated sample, were analyzed by GC (gas chromatography); the GC area analysis is summarized in Table 1.

[0374] Table 1: GC area analysis of the reaction between succinic anhydride and ethyl 3-hydroxybutyrate [%)

[0375] Before fractionation Fraction A Fraction B 3-BHB-EE 0.9 - - 3-BHB 0.1 - - Succinic acid 1.5 - - 3-BHB derivatives* 2.1 0.11 - BS-(BHB-EE) monoester 77.7 97.6 0.23 BS-(BHB-EE)-dieser 14.7 - 94.39 Byproducts** 1.6 1.44 4.56 unknown 1.6 0.84 0.82

[0376] *Various 3-BHB derivatives (e.g., oligomers such as dimers, trimers, and tetramers).

[0377] Various oligomers and polycondensation derivatives of BS-(BHB-EE) and BS derivatives (e.g., dimers, trimers, diesters, and polyesters, respectively).

[0378] To further characterize fractions A and B, measurements were taken. 1 H-NMR and 13 C NMR spectra and 2 D-NMR spectra (COSY, HSQC, HMBC). The spectra show (as with GC analysis) that fraction A contains succinate monoester of ethyl 3-hydroxybutyric acid, and fraction B contains succinate diester of ethyl 3-hydroxybutyric acid.

[0379] The structure of ethyl 3-hydroxybutyrate succinate monoester (from fraction A) is shown below, and is labeled with... 1 H-NMR signal (1) and 13 The uniquely assignable chemical shift in the NMR spectrum of the C-NMR signal (2):

[0380]

[0381]

[0382] The structure of the succinate diester of ethyl 3-hydroxybutyric acid (from fraction B) is shown below, and is labeled with... 1 H-NMR signal (3) and 13 The uniquely assignable chemical shift in the NMR spectrum of the C-NMR signal (4):

[0383]

[0384]

[0385] Subsequently, fractions A and B were further purified (e.g., by chromatography). In the case of fraction A, pure ethyl 3-hydroxybutyrate succinate monoester (purity > 99%) was obtained, and in the case of fraction B, pure ethyl 3-hydroxybutyrate succinate diester (purity > 99%) was obtained. A 1:1 mixture of monoester / diester was also prepared from a portion of the purified esters.

[0386] IV.2 Reaction of citric acid with ethyl 3-hydroxybutyrate

[0387] In a 500 mL multi-necked flask equipped with a fractionating distillation apparatus (partial condenser) and a distillation bridge, 599 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 146 g of citric acid were reacted at 130 °C and 70 mbar. After a 26-hour reaction time, 67 mg of tetrabutyl titanate (titanium(IV)-catalyst) was added to the reaction mixture, and after another 3 hours of reaction time, an additional 43 mg of tetrabutyl titanate (titanium(IV)-catalyst) was added to the reaction mixture. The reaction mixture was then allowed to react for another 6 hours.

[0388] Throughout the reaction time, samples were periodically taken and their composition analyzed. The resulting conversion time process is as follows: Figure 2 As shown.

[0389] The conversion time process shows that initially, ethyl 3-hydroxybutyric acid monoester and citrate diester were significantly formed. The conversion rate was slightly improved upon the first addition of titanium (IV) catalyst; however, the second addition did not lead to a further significant increase in conversion rate.

[0390] The purified product mixture was used for further analysis. First, excess 3-BHB-EE was removed, and then the residue was purified by column chromatography. To identify the structure of ethyl 3-hydroxybutyrate citrate, the individual esters were separated by column chromatography. For this purpose, the product mixture was chromatographically analyzed on a silica gel-packed column using a 5 / 3 mixture of ethyl acetate / cyclohexane with 0.7% glacial acetic acid as the running medium. Subsequently, fractions A and B, as well as unfractionated samples before and after removal of excess 3-BHB-EE, were analyzed by GC (gas chromatography); the GC area analysis is summarized in Table 2.

[0391] Table 2: GC area analysis of the reaction between citric acid and ethyl 3-hydroxybutyrate [%)

[0392]

[0393] *Various 3-BHB derivatives (e.g., oligomers such as dimers, trimers and tetramers; deprotonated derivatives such as acetoacetate, etc.).

[0394] Various oligomers and polycondensation derivatives of CS-(BHB-EE) and CS derivatives (e.g., each dimer, trimer, diester, and polyester, etc.).

[0395] GC analysis showed that the main products were citrate diesters and triesters of 3-hydroxybutyric acid; that is, the 3-hydroxybutyric acid citrate monoester was almost completely converted into the corresponding diester. Fraction A mainly contained citrate diester of 3-hydroxybutyric acid, and fraction B mainly contained citrate diester of 3-hydroxybutyric acid.

[0396] To further characterize fraction A, measurements were taken. 1 H-NMR and 13 C-NMR spectra and 2 D-NMR spectroscopy (COSY, HSQC, HMBC). The spectra show (as with GC analysis) that fraction A contains ethyl 3-hydroxybutyric acid triester of citrate. Three distinct stereocenters produce four diastereomers, resulting in numerous signals in each group. The isomer mixture itself is of high purity.

[0397] The structure of the tricitrate ester of ethyl 3-hydroxybutyric acid (from fraction A) is shown below, and is labeled with... 1 H-NMR signal (5) and 13 The chemical shift uniquely specified by the NMR spectrum of the C-NMR signal (6):

[0398]

[0399]

[0400] Subsequently, fractions A and B were further purified (e.g., by chromatography). In the case of fraction A, pure ethyl 3-hydroxybutyrate citrate triester (purity > 99%) was obtained, and in the case of fraction B, a mixture of ethyl 3-hydroxybutyrate citrate diester and citrate monoester (purity > 99%) was obtained. A 1:1:1 mixture of monoester / diester / triester was also prepared from a portion of the purified esters.

[0401] IV.3. Reaction of malic acid with ethyl 3-hydroxybutyrate

[0402] In a 500 mL multi-necked flask equipped with a fractionating distillation apparatus (partial condenser) and a distillation bridge, 476 g of (R) / (S)-3-hydroxybutyrate ethyl ester (3-BHB-EE = ethyl 3-hydroxybutyrate or 4-ethoxy-4-oxobut-2-ol) (racemic) and 121 g of malic acid were reacted at 120 °C and 70 mbar for 10 h. Subsequently, 100 g was removed, and the remainder was further reacted. After 4 hours of reaction, the reaction mixture was cooled to 100 °C, and 100 mg of tetrabutyl titanate (titanium(IV)-catalyst) was added to the reaction mixture. The reaction was then reheated to 120 °C and stirred at a constant temperature and 60 mbar for another 24 h. After 18 hours of reaction, fresh tetrabutyl titanate (titanium(IV)-catalyst) was added.

[0403] Throughout the reaction time, samples were periodically taken and their composition analyzed. The resulting conversion time process is as follows: Figure 3 As shown.

[0404] From the perspective of the conversion time process, the addition of titanium (IV) catalyst obviously does not lead to a significant increase in conversion rate.

[0405] The removed 100g of reaction mixture was purified for further analysis. For this purpose, excess 3-BHB-EE was first removed, followed by purification of the group by column chromatography. The product mixture was analyzed chromatographically on a silica gel-packed column using a 2 / 1 mixture of ethyl acetate and cyclohexane containing 1% glacial acetic acid as the running medium. Subsequently, fractions A and B, as well as unfractionated samples before and after removal of excess 3-BHB-EE, were analyzed by GC (gas chromatography); the GC area analysis is summarized in Table 3.

[0406] Table 3: GC area analysis of the reaction between malic acid and ethyl 3-hydroxybutyrate [%)

[0407] Before fractionation Fraction A Fraction B 3-BHB-EE 22.9 0.8 0.8 3-BHB 0.5 - - Succinic acid 0.6 - 1.1 malic acid 13.5 - 0.5 3-BHB derivatives* 5.6 3.0 - BS-(BHB-EE) monoester 0.9 5.1 - Malic acid (BHB-EE) monoester 33.3 0.2 88.9 malic acid dimer 2.4 3.4 - Malic acid (BHB-EE) diester 11.3 73.1 4.6 Byproducts** 7.2 11.9 1.2 unknown 1.9 2.5 1.2

[0408] *Various 3-BHB derivatives (e.g., oligomers such as dimers, trimers, and tetramers).

[0409] Various oligomeric and polycondensed malic acid (BHB-EE) derivatives, as well as malic acid derivatives (e.g., various dimers, trimers, diesters, and polyesters).

[0410] To further characterize fractions A and B, measurements were taken. 1 H-NMR and 13 C-NMR spectra and 2 D-NMR spectra (COSY, HSQC, HMBC). The spectra show (same as GC analysis) that fraction A contains malate diester of ethyl 3-hydroxybutyric acid, and fraction B contains malate monoester of ethyl 3-hydroxybutyric acid.

[0411] The structure of the malate diester of ethyl 3-hydroxybutyric acid (from fraction A) is shown below, and is labeled with... 1 H-NMR signal (7) and 13 The chemical shift uniquely specified by the NMR spectrum of the C-NMR signal (8):

[0412]

[0413]

[0414] The structure of the malate diester of ethyl 3-hydroxybutyric acid (from fraction B) is shown below, and is labeled with... 1 H-NMR signal (9) and 13 The uniquely assignable chemical shift in the NMR spectrum of the C-NMR signal (10):

[0415]

[0416]

[0417] Subsequently, fractions A and B were further purified (e.g., by chromatography). In the case of fraction A, pure ethyl 3-hydroxybutyrate malate diester (purity > 99%) was obtained, and in the case of fraction B, pure ethyl 3-hydroxybutyrate malate monoester (purity > 99%) was obtained. A 1:1 mixture of monoester / diester was also prepared from a portion of the purified esters.

[0418] V. Physiological Application Tests: In Vitro Digestion Tests

[0419] V.1. Digestion experiment (fracture or cleavage test) of the 3-hydroxybutyric acid carboxylic acid ester of the present invention.

[0420] The cleavage experiments showed that the 3-hydroxybutyric acid carboxylic acid ester or mixture thereof prepared according to the present invention (see the previously described experiments according to I, II and III), including reaction byproducts such as dimers, can be cleaved in the human gastrointestinal tract.

[0421] In each case, the purified reaction product obtained by the method of the present invention is used as the starting mixture (i.e., 3-hydroxybutyrate tartrate, 3-hydroxybutyrate lactate, 3-hydroxybutanol succinate, 3-hydroxybutyrate citrate, 3-hydroxybutyrate maleate, 3-hydroxybutyrate fumarate, 3-hydroxybutyrate malate, and 3-hydroxybutyrate adipate).

[0422] For lysis experiments under near-bulk conditions, two media were studied:

[0423] •FaSSGF, a stomach simulator;

[0424] FaSSIF, a gut analogue.

[0425] Both media originated from the UK. Ltd. In addition, in some experiments, porcine pancreas ( Fa.Allergan).

[0426] Use in FaSSGF or FaSSIF media and not using The pyrolysis test results (all at 35℃, 24 hours) showed that the sample, when used... and not using Hydrolysis occurs under FaSSGF conditions; this is primarily due to the low pH of the medium (pH = 1.6). Under FaSSIF conditions, using The conversion rate is low.

[0427] In the cleavage experiment of, for example, 3-hydroxybutyric acid triester citrate, it can be seen that the cleavage of 3-hydroxybutyric acid is a cascade process (i.e., the triester citrate becomes the diester citrate, the diester citrate becomes the monoester citrate, and the monoester citrate finally becomes free citric acid, wherein the corresponding 3-hydroxybutyrate is released in each step, which can then be further cleaved to give free 3-hydroxybutyric acid and ethanol).

[0428] Therefore, the cleavage experiments of 3-hydroxybutyrate dicarboxylic acid ester were also carried out in a cascade. Thus, an overall delayed effect exists.

[0429] V.2. Further digestion experiments (cleavage experiments) of the 3-hydroxybutyric acid carboxylic acid ester of the present invention.

[0430] Using trypsin lysis experiment

[0431] Dissolve 2 g of the 3-hydroxybutyric acid carboxylic acid ester or mixture thereof prepared as described above (e.g., a mixture of mono- and di- or mono-, di- and tricarboxylic acid esters of the corresponding 3-hydroxybutyric acid) in 50 g of water, and add 0.5 g (1 wt%) of trypsin. The trypsin is a commercially available product from Allergan. The mixture was used in the form of [missing information]. The entire mixture was stirred on a hot plate at 50°C; the reaction process was observed, and the acid value was continuously recorded over time. The acid value increased during the observation period (the carboxylic acid ester of 3-hydroxybutyric acid was cleaved into free 3-hydroxybutyric acid). The conversion time process of the aqueous cleavage of the 3-hydroxybutyric acid carboxylic acid ester by the pancreatic enzyme according to the invention, including the increase in acid value over time, demonstrates that the reactant mixture is expected to decompose into free carboxylic acid and free 3-hydroxybutyric acid. This was confirmed by appropriate analysis. Experiments have shown that the starting mixture of the invention is a suitable physiological precursor of 3-hydroxybutyric acid or its ester (3-hydroxybutyrate) for corresponding ketone body therapy.

[0432] The tests were repeated and validated based on individual esters in their pure form. Similar results were obtained in each case, namely that 3-hydroxybutyrate carboxylic acid esters were cleaved by trypsin into free carboxylic acid and 3-hydroxybutyrate or 3-hydroxybutyric acid.

[0433] V.3 Conclusion

[0434] The previously described cleavage experiments demonstrate that 3-hydroxybutyrate carboxylic acid esters are effective precursors or metabolites of free hydroxybutyric acid or its esters (here: ethyl ester, hydroxybutyl ester, and hydroxypentyl ester), particularly in their physiologically tolerable or physiologically compatible form with respect to their intended effects. Similarly, metabolically available or convertible carboxylic acids or their derivatives, particularly salts (e.g., citric acid or citrate, malic acid or malate, tartaric acid or tartrate, etc.), are formed in natural metabolism (e.g., the citrate cycle).

[0435] VI. Further testing (sensory and toxicological)

[0436] Further experiments and a series of tests were conducted regarding the sensory properties and toxicity of the 3-hydroxybutyric acid carboxylate according to the invention. These results indicate that the 3-hydroxybutyric acid carboxylate according to the invention is sensorily acceptable and compatible, and exhibits particularly significantly improved sensory properties compared to pure 3-hydroxybutyric acid and its salts and esters, and also shows no toxicity contrary to its application.

Claims

1. A method for preparing 3-hydroxybutyric acid carboxylic acid ester, At least one 3-hydroxybutyrate of general formula (I) reacts with at least one carboxylic acid (II) in an esterification reaction, said carboxylic acid (II) being selected from the group consisting of succinic acid, tartaric acid, lactic acid, citric acid, malic acid, adipic acid, fumaric acid, and maleic acid, as well as their salts, anhydrides, and esters, and combinations or mixtures thereof. CH3-CH(OH)-CH2-C(O)OR 1 (I) in, In general formula (I), group R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl, The reaction described herein is carried out without any solvent. The reaction is carried out in the absence of any catalyst, or in the presence of an enzyme acting as a catalyst. Thus, as reaction product (III), one or more 3-hydroxybutyric acid carboxyl esters are obtained.

2. The method according to claim 1, The carboxylic acid (II) therein is used in the form of a free carboxylic acid, a carboxylate, a carboxylic acid ester, or a carboxylic anhydride.

3. The method according to claim 1, The molar amount of the 3-hydroxybutyrate of general formula (I) based on the carboxyl group of the carboxylic acid (II) is in the range of equimolar amount to 200 mol% molar excess.

4. The method according to claim 1, The 3-hydroxybutyrate of general formula (I) and the carboxylic acid (II) are used in a molar ratio of 3-hydroxybutyrate of general formula (I) to carboxylic acid (II), the molar ratio being in the range of 1:1 to 10:

1.

5. The method according to claim 1, The hydroxyl and carboxyl groups that remain in the reaction product after the reaction is completed are at least partially esterified.

6. A 3-hydroxybutyric acid carboxylic acid ester, 3-hydroxybutyric acid carboxylic acid ester corresponds to general formula (IIIb). CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb) In general formula (IIIb), ·Group R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl, and ·Group R 4 Selected from one or more of the following groups in, In the stated group, group R 5 This indicates hydrogen or the group -CH(CH3)-CH2-C(O)OR 1 R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl.

7. The 3-hydroxybutyric acid carboxylic acid ester according to claim 6, In general formula (IIIb), ·Group R 1 Selected from ethyl, butyl, pentyl, hydroxybutyl, and hydroxypentyl, and ·Group R 4 Selected from one or more of the following groups in, In the stated group, group R 5 This indicates hydrogen or the group -CH(CH3)-CH2-C(O)OR 1 R 1 It is selected from ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl.

8. A mixture comprising at least two different carboxylic acid esters (III) of 3-hydroxybutyric acid as described in claim 6.

9. A pharmaceutical composition comprising at least one carboxylic acid ester (III) of 3-hydroxybutyric acid, Among them, 3-hydroxybutyric acid carboxylic ester (III) corresponds to general formula (IIIb), CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb) In general formula (IIIb), ·Group R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl, and ·Group R 4 Selected from one or more of the following groups in, In the stated group, group R 5 This indicates hydrogen or the group -CH(CH3)-CH2-C(O)OR 1 R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl.

10. The pharmaceutical composition according to claim 9, In general formula (IIIb), ·Group R 1 Selected from ethyl, butyl, pentyl, hydroxybutyl, and hydroxypentyl, and ·Group R 4 Selected from one or more of the following groups in, In the stated group, group R 5 This indicates hydrogen or the group -CH(CH3)-CH2-C(O)OR 1 R 1 It is selected from ethyl, butyl, pentyl, hydroxybutyl or hydroxypentyl.

11. The pharmaceutical composition according to claim 9, The pharmaceutical composition thereon is a drug or pharmaceutical preparation.

12. A food product comprising at least one carboxylic acid ester (III) of 3-hydroxybutyric acid, Among them, 3-hydroxybutyric acid carboxylic ester (III) corresponds to general formula (IIIb), CH3-CH(OR 4 )-CH2-C(O)OR 1 (IIIb) In general formula (IIIb), ·Group R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl, and ·Group R 4 Selected from one or more of the following groups in, In the stated group, group R 5 This indicates hydrogen or the group -CH(CH3)-CH2-C(O)OR 1 R 1 Selected from C1-C5 alkyl and hydroxy-C3-C5-alkyl.

13. The food product according to claim 12, The food mentioned therein is selected from the group consisting of food, dietary supplements, functional foods, novel foods, food additives, food supplements, dietary foods, energy snacks, appetite suppressants, strength training supplements, and endurance training supplements.

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