Method for producing hydroxycarboxylic acid fatty alcohol ester

Abstract

The present invention relates to a method for producing fatty alcohol esters of 3-hydroxybutyric acid and acylated derivatives thereof, and products obtained thereby and uses thereof.

Description

Technical Field

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

[0002] In particular, the present invention relates to a method for producing 3-hydroxybutyric acid fatty alcohol esters, as well as the reaction products obtained or prepared thereby (i.e. 3-hydroxybutyric acid fatty alcohol esters) and their uses, in particular in pharmaceutical compositions (e.g. drugs (pharmaceuticals) or medicaments) or in foods and / or foods, and their further applications or uses.

[0003] The present invention also relates to a process for producing acylated (e.g. acetylated) 3-hydroxybutyric acid fatty alcohol esters (i.e., in other words, fatty alcohol esters of 3-acyloxybutyric acid (e.g., 3-acetoxybutyric acid)), the reaction products obtained or prepared thereby (i.e., acylated 3-hydroxybutyric acid fatty alcohol esters, i.e., fatty alcohol esters of 3-acyloxybutyric acid (e.g., 3-acetylbutyric acid)) and their use, in particular in pharmaceutical compositions (e.g., drugs (medicines) or medicaments) or in foods and / or foodstuffs, and their further applications or uses.

[0004] Furthermore, the present invention relates to pharmaceutical compositions, in particular drugs (medicines) or medicaments, comprising the reaction products obtainable or produced according to the process of the present invention (i.e. fatty alcohol esters of 3-hydroxybutyric acid and acylated derivatives thereof), and their use or uses.

[0005] Finally, the present invention relates to foods and / or foodstuffs, in particular food supplements, functional foods, novel foods, food additives, food supplements, dietary foods, energy snacks, appetite suppressants and strength and / or endurance sports supplements, which contain the reaction product obtainable or produced according to the process of the present invention (i.e. fatty alcohol esters of 3-hydroxybutyric acid and acylated derivatives thereof), and their applications or uses. Background Art

[0006] In human energy metabolism, glucose is a short-term available energy carrier that is metabolized to energy in the mitochondria by releasing water and carbon dioxide. The liver's glycogen reserves are already emptied during sleep at night. However, the human central nervous system (CNS) and heart in particular require a permanent energy supply.

[0007] The main physiological substitutes for glucose available to the central nervous system are the so-called ketone bodies.

[0008] The term ketone bodies is in particular a general term for three compounds which are formed primarily in catabolic states (such as starvation, reduced diet or low-carbohydrate diet) and which may lead to ketosis. The term ketone bodies particularly includes three compounds: acetoacetate (also synonymously referred to as acetoacetate) and acetone as well as 3-hydroxybutyric acid (hereinafter also synonymously referred to as β-hydroxybutyric acid or BHB or 3-BHB) or its salts (i.e. 3-hydroxybutyric acid salts or β-hydroxybutyric acid salts), the latter being the most important of the three compounds mentioned above. 3-Hydroxybutyric acid or its salts occurs physiologically as the (R)-enantiomer, i.e. as (R)-3-hydroxybutyric acid (also synonymously referred to as (3R)-3-hydroxybutyric acid to emphasize the chiral center at the 3-position) or its salts.

[0009] These ketone bodies are also physiologically provided in large quantities during fasting or starvation through lipolysis of stored lipids in the body and almost completely replace the energy source glucose.

[0010] The ketone bodies formed in the liver come from acetyl-CoA (= acetyl-CoA), which originate from beta oxidation; they are a transportable form of acetyl-CoA in the body. However, in order to utilize ketone bodies, the brain and muscles must first adapt by expressing the enzymes required to convert ketone bodies back into acetyl-CoA. Especially in times of starvation, ketone bodies contribute greatly to energy production. For example, after a while, the brain can only survive on one third of the daily glucose intake.

[0011] Physiologically, ketone bodies are synthesized from activated acetic acid in the form of two molecules of acetyl-CoA, a normal intermediate in the degradation of fatty acids, which is expanded to the intermediate 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) using further acetyl-CoA units and the enzyme HMG-CoA-synthetase, where finally HMG-CoA-lyase cleaves acetoacetate. These three steps occur exclusively in the mitochondria of the liver (ranin cycle), where 3-hydroxybutyrate is ultimately formed in the cytosol by 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.

[0012] Spontaneous decarboxylation converts acetoacetate to acetone; it is occasionally 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.

[0013] Thus, acetoacetate is reductively converted to the physiologically relevant form of 3-hydroxybutyrate or 3-hydroxybutyrate, but can also be decomposed into acetone, which is physiologically unusable, and releases carbon dioxide, which can be detected and olfactorily perceived in the urine and exhaled air of patients with severe ketosis, ketoacidosis (e.g., patients with type 1 diabetes without insulin replacement).

[0014] 3-Hydroxybutyrate is currently used and sold in the weight training field as a sodium, magnesium, or calcium salt.

[0015] However, from an evolutionary perspective, humans do not know 3-hydroxybutyrate, or know very little, because plants do not produce 3-hydroxybutyrate, and 3-hydroxybutyrate in animals only appears in emaciated animals that die in ketosis, so 3-hydroxybutyrate causes nausea when administered orally. 3-hydroxybutyrate in the form of free acid and its salts also taste bitter and can cause severe vomiting and nausea.

[0016] Furthermore, patients (especially newborns, but also adults) cannot tolerate large amounts of salts of 3-hydroxybutyric acid for long periods of time, since these compounds can have a renal-damaging effect.

[0017] In addition, the plasma half-life of 3-hydroxybutyric acid and its salts is very short, and even if a few grams are taken, ketosis only lasts for about three to four hours, i.e., patients cannot benefit continuously from treatment with 3-hydroxybutyric acid or its salts, especially at night. In the case of metabolic diseases, this can lead to life-threatening situations.

[0018] Therefore, in the context of the treatment of such metabolic diseases, so-called medium-chain triglycerides, so-called MCTs, are currently used in ketogenic therapy, i.e. caproic acid, caprylic acid and capric acid (i.e. saturated linear C6-, C8- and C9-containing triglycerides) are expected to be derived from the corresponding triglycerides. 10 - fatty acids) metabolic conversion.

[0019] However, fundamentally, from a pharmaceutical and clinical point of view, 3-hydroxybutyrate is a more effective pharmaceutical-pharmacological target molecule, which, according to the prior art, can in principle be used to treat a variety of diseases, but cannot be used due to lack of physiological compatibility (e.g. diseases related to disorders of energy metabolism, in particular ketone body metabolism, or neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, etc., fat metabolism diseases, etc.).

[0020] The table below illustrates potential therapeutic options or possible indications for the active ingredient 3-hydroxybutyric acid by way of example only and not by way of limitation.

[0021]

[0022]

[0023] Therefore, from a pharmaceutical and clinical point of view, it is desirable to be able to find effective precursors or metabolites which physiologically allow direct or indirect access to 3-hydroxybutyric acid or its salts, in particular in the physiological metabolism of the human or animal body.

[0024] Therefore, the prior art is not lacking in attempts 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. In addition, according to the prior art, it is impossible or not easily possible to obtain such compounds. Summary of the invention

[0025] Therefore, the problem underlying the present invention is to provide an efficient process for producing physiologically suitable or physiologically compatible precursors and / or metabolites of 3-hydroxybutyrate (ie β-hydroxybutyrate or BHB or 3-BHB) or salts thereof.

[0026] Such a process should in particular enable the corresponding BHB precursors and / or BHB metabolites to be obtained in an efficient manner, in particular in large quantities and without large amounts of toxic by-products.

[0027] In a completely surprising manner, the Applicant has now discovered that fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) and fatty alcohol esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) represent efficient and physiologically effective or physiologically compatible precursors and / or metabolites of the keto body 3-hydroxybutyric acid or its salts, and has here been able to find or develop efficient processes for the production of these compounds which allow direct and efficient, in particular economically and industrially viable, access to these compounds.

[0028] In order to solve the above-mentioned problems, according to a first aspect of the present invention, the present invention therefore proposes a method for producing fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) according to claim 1; in addition, particularly special and / or advantageous embodiments of the method of the present invention are the subject matter of the relevant dependent claims.

[0029] Furthermore, according to a second aspect of the present invention, the present invention relates to reaction products obtainable by the process according to the invention according to the independent claims (claims 39 and 40), or fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) according to the corresponding claims (claims 41 to 46), as well as reaction intermediates obtainable by the process according to the invention according to the independent claim (claim 47), or fatty alcohol esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the corresponding claims (claims 48 to 52); particularly particular and / or advantageous embodiments of this aspect of the present invention are furthermore the subject matter of the respective dependent claims.

[0030] Similarly, according to a third aspect of the invention, the present invention relates to a pharmaceutical composition, in particular a drug (medicine) or a medicament, according to the corresponding independent claim (claim 53); in addition, particularly special and / or advantageous embodiments of this aspect of the invention are the subject of the relevant dependent claims.

[0031] Furthermore, according to a fourth aspect of the invention, the present invention relates to reaction products according to the invention of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) or fatty alcohol esters according to the invention and reaction intermediates according to the invention of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) or fatty alcohol esters according to the invention according to the corresponding independent claim (claim 55), in each case for use in the prophylactic and / or therapeutic treatment or in each case for use in the prophylactic and / or therapeutic treatment of diseases of the human or animal body.

[0032] Furthermore, according to a fifth aspect of the invention, the present invention relates to the use of the reaction products of the invention of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) or the fatty alcohol esters of the invention and of the reaction intermediates of the invention of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) or the fatty alcohol esters of the invention according to the relevant independent claim (claim 56), in each case for the prophylactic and / or therapeutic treatment or in each case for the production of a medicament for the prophylactic and / or therapeutic treatment of diseases of the human or animal body.

[0033] Furthermore, according to a sixth aspect of the invention, the present invention relates to the use of the reaction products of the invention of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) or the fatty alcohol esters of the invention, as well as the reaction intermediates of the invention of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) or the fatty alcohol esters of the invention according to the relevant independent claim (claim 57), in each case for prophylactic and / or therapeutic treatment, or in each case for the production of a medicament for prophylactic and / or therapeutic treatment, or for use in catabolic states.

[0034] Furthermore, according to a seventh aspect of the present invention, the present invention relates to food and / or food products according to the relevant independent claim (claim 58); furthermore, particularly special and / or advantageous embodiments of the food and / or food products according to the present invention are the subject of the relevant dependent claims.

[0035] Finally, according to an eighth aspect of the present invention, the present invention relates to the use of the reaction products of the present invention of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) or the fatty alcohol esters of the present invention and the reaction intermediates of the present invention of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) or the fatty alcohol esters of the present invention in foods and / or foods; in addition, particularly specific and / or advantageous embodiments of the use according to the present invention are the subject matter of the use-related dependent claims.

[0036] It goes without saying that, in order to avoid repetition, the following features, embodiments, advantages, etc., which are listed below for only one aspect of the present invention, naturally also apply to other aspects of the present invention accordingly without separate mention.

[0037] Furthermore, it goes without saying that the individual aspects and embodiments of the invention are also regarded as disclosed in any combination with other aspects and embodiments of the invention, in particular any combination of features and embodiments, since back-references from all patent claims are also regarded as a comprehensive disclosure with regard to all resulting combination possibilities.

[0038] With regard to all relative or percentage data based on weight provided below, in particular relative amounts or weight data, it should also be noted that, within the scope of the present invention, these will be selected by the person skilled in the art so that they always add up to 100% or 100% by weight, respectively, including in particular all components or ingredients as defined below; however, this is self-evident for the person skilled in the art.

[0039] Furthermore, the skilled artisan may deviate from the following range specifications, if necessary, without departing from the scope of the present invention.

[0040] Furthermore, all values ​​or parameters etc. specified below apply which can in principle be determined or identified using standardized or clearly defined determination methods or other determination or measurement methods with which the person skilled in the art is familiar.

[0041] Having said this, the present invention will be described in more detail below:

[0042] According to a first aspect of the invention, the subject of the invention is therefore a process for producing fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB),

[0043] (A) wherein, according to the (first) synthetic route (A), at least one compound of the general formula (Ia) is combined with a compound selected from C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - at least one fatty alcohol (II) of a fatty alcohol is reacted,

[0044] CH3-CH(OH)-CH2-C(O)R 1 (Ia)

[0045] Among them, in the general formula (Ia), the group R 1 represents hydrogen or C1-C4-alkyl, in particular C1-C4-alkyl, preferably methyl or ethyl, more preferably ethyl;

[0046] or

[0047] (B) wherein, according to the (second, alternative (A)) synthetic route (B), at least one compound of formula (Ib) is combined with a compound selected from C 10 -C30 - fatty alcohols, especially C 10 -C 24 - at least one fatty alcohol (II) of a fatty alcohol is reacted and then the acyl group is hydrolyzed,

[0048] CH3-CH(OR 2 )-CH2-C(O)-OC(O)-CH2-CH(OR 2 )-CH3 (Ib)

[0049] In the general formula (Ib), the group R 2 represents an acyl group selected from -C(O)-CH3(acetyl) or -C(O)-C2H5(propionyl), preferably -C(O)-CH3(acetyl);

[0050] Thus, as reaction product (III), in each case C of 3-hydroxybutyric acid is obtained. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - Fatty alcohol esters.

[0051] As described above, the applicant has surprisingly discovered that fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) (among others, also synonymously referred to as "3-hydroxybutyric acid fatty alcohol esters" etc.) and the reaction intermediates before acyl hydrolysis according to synthesis route (B) (i.e., acylated 3-hydroxybutyric acid fatty alcohol esters or 3-acyloxybutyric acid fatty alcohol esters) are each effective as physiologically compatible precursors and / or metabolites of 3-hydroxybutyric acid or its salts, which can also be used in large quantities in medical or clinical applications because they are physiologically compatible.

[0052] The above-mentioned fatty alcohol esters of 3-hydroxybutyric acid or acylated fatty alcohol esters of 3-hydroxybutyric acid, which are effectively obtainable for the first time by the production process according to the invention, represent physiologically and pharmacologically relevant alternatives to free 3-hydroxybutyric acid or its salts.

[0053] The production of 3-hydroxybutyric acid or acylated fatty alcohol esters of 3-hydroxybutyric acid by conventional organic synthesis is complicated and cost-intensive, since 3-hydroxybutyric acid has an increased tendency to polymerize and undergo other undesirable side reactions (e.g. dehydration, decomposition, etc.). Within the scope of the present invention, for the first time an efficiently functioning production process is provided by which 3-hydroxybutyric acid or acylated fatty alcohol esters of 3-hydroxybutyric acid can be produced, in particular in one step, without undesirable side reactions.

[0054] Thus, the method according to the invention makes it possible for the first time to provide non-toxic 3-hydroxybutyric acid or acylated 3-hydroxybutyric acid fatty alcohol esters from known, commercially available and in particular physiologically harmless components or educts (starting compounds). The 3-hydroxybutyric acid or acylated 3-hydroxybutyric acid fatty alcohol esters produced thereby can be physiologically decomposed, in particular in the stomach and / or intestine, and release or produce the target molecule "3-hydroxybutyric acid" or its salt as active ingredient or active component.

[0055] Furthermore, the above-mentioned fatty alcohol esters of 3-hydroxybutyric acid or acylated 3-hydroxybutyric acid also contain an acceptable taste to ensure compatibility even when orally administered in larger amounts over a longer period of time (e.g., a daily dosage of 50 g or more).

[0056] Similarly, according to the production method of the present invention, it is possible to provide 3-hydroxybutyric acid or fatty alcohol ester of acylated 3-hydroxybutyric acid free of toxic impurities.

[0057] Furthermore, with suitable starting materials, the process can also be carried out enantioselectively. For example, according to the invention, the production process allows the biologically relevant form (i.e. the (R)-enantiomer) to be enriched, in particular by enzyme catalysis, so that in the case of oral administration, the patient's renal system is not burdened (i.e. removed by the kidneys). However, in principle, enrichment of the (S)-enantiomer is also possible and may be useful under certain conditions.

[0058] Furthermore, the production process according to the invention, including optional further processing or purification steps, can be operated economically and can also be implemented on a large scale.

[0059] In particular, the production method of the present invention uses commercially available or easily obtained starting compounds and furthermore allows relatively simple process management even when carried out on a large scale.

[0060] In contrast to conventional prior art production methods, the production method according to the invention does not use complex starting materials and uses only a single step. However, excellent yields are achieved according to the invention, wherein the formation of by-products is minimized or avoided.

[0061] Furthermore, the process of the invention is simple and economical. In particular, the process according to the invention is usually carried out without solvent and / or without any solvent (i.e. as a mass reaction or as a substance reaction or as a so-called bulk reaction); therefore, the reaction product obtained is not contaminated by the solvent and after carrying out the process or reaction, there is no need to remove and dispose of or recycle the solvent in an expensive and energy-consuming manner. Furthermore, no toxic by-products are formed.

[0062] If desired, the crude reaction product obtained in the production process according to the invention can be purified in a simple manner and without further treatment, in particular by known methods, in particular by removing any remaining starting compounds and / or any by-products present (for example by distillation and / or chromatography, etc.).

[0063] Synthesis route (A)

[0064] The following is a review of the synthetic route (A) involved in the process of the present invention.

[0065] According to a particular embodiment of the present invention, according to the synthesis route (A), the compound of general formula (Ia) can be used in racemic form or in the form of (R)-enantiomers. The (R) configuration refers to the chiral carbon atom at position 3 of the compound of general formula (Ia).

[0066] According to the present invention, preferably, according to the synthesis route (A), in the general formula (I), the group R 1 Represents ethyl.

[0067] In other words, it is preferred according to the present invention that, according to the synthesis route (A), ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate) of the formula CH3-CH(OH)-CH2-C(O)OC2H5 is used as the compound of the general formula (Ia).

[0068] This makes possible particularly effective process control and high yields with minimization or suppression of the formation of by-products. In addition, ethyl 3-hydroxybutyrate is also commercially available in large quantities and can also be converted more effectively than the free acid (i.e. 3-hydroxybutyric acid). In particular, ethyl 3-hydroxybutyrate can be obtained on a large scale as a starting compound, for example by the Claisen condensation of ethyl acetate.

[0069] Especially, in the inventive method, according to synthetic route (A), reaction is carried out in the absence of solvent and / or in the absence of any solvent. This means that the reaction is carried out with mass reaction, material reaction or so-called bulk reaction. The advantage of doing so is that the obtained reaction product is not polluted by solvent, and after carrying out the method or reaction, there is no need to remove and dispose of or recycle solvent in an expensive and energy-consuming manner. Surprisingly, the method or reaction is still carried out with high conversion and yield, and at least substantially without significant by-product formation.

[0070] According to a particular embodiment of the present invention, according to synthetic route (A), the reaction can be carried out in the presence of a catalyst, in particular an enzyme and / or an acidic or alkaline catalyst containing metal and / or metal groups, preferably in the presence of an enzyme. In this particular embodiment, it is preferred that the catalyst is recycled after the reaction.

[0071] As described above, according to the present invention, the reaction can be carried out in the presence of an enzyme as a catalyst.

[0072] In this respect, the enzyme may in particular be selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof. According to the invention, synthetases (ligases) are in particular enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by covalent bonds. Catalase in the sense of the invention is in particular an enzyme that is able to convert hydrogen peroxide into oxygen and water. The term esterase refers in particular to enzymes that are able to hydrolytically split esters into alcohols and acids (saponification); these are therefore in particular hydrolases, wherein lipolytic esterases are also referred to as lipases. Lipases in the sense of the invention are in particular enzymes that are able to separate free fatty acids from lipids such as glycerides (lipolysis).

[0073] Within the scope of the present invention, according to synthesis route (A), the enzyme used as catalyst can be derived in particular from Candida antarctica, Mucor miehei (Mucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus dei olivinei and Pseudomonas, and combinations thereof, preferably from Candida antarctica, Mucor miehei (Mucor miehei) and Thermomyces lanuginosus.

[0074] According to one embodiment, according to synthesis route (A), the enzyme can be used in an immobilized form, immobilized on a carrier, preferably on a polymer carrier, preferably on a polymer organic carrier, more preferably having hydrophobicity, even more preferably on a poly(meth)acrylic resin-based carrier.

[0075] As explained above in relation to the general use of catalysts, when an enzyme is used as catalyst according to synthesis route (A), it is preferred to recycle the enzyme after the reaction.

[0076] According to this particular embodiment of the process of the invention, according to synthesis route (A), the respective commercially available enzymes defined above can be used as the enzymes described above (e.g. CALB lipase derived from Candida antarctica on a polymer support, e.g. , CALB lipase from Sigma Aldrich or Merck). 435, or from Strem Chemicals, Inc. Strem 435).

[0077] If the reaction according to the synthesis route (A) is carried out in the presence of an enzyme as a catalyst within the framework of the production process according to the invention, the reaction is preferably carried out at a temperature in the range of 10°C to 80°C, in particular in the range of 20°C to 80°C, preferentially in the range of 25°C to 75°C, more preferably in the range of 45°C to 75°C, still more preferably in the range of 50°C to 70°C.

[0078] In the case of using an enzyme as a catalyst, the amount of the enzyme used can vary over a wide range, depending on the synthetic route (A). In particular, based on the total amount of starting compounds (Ia) and (II), the amount of the enzyme can be in the range of 0.001 wt % to 20 wt %, in particular in the range of 0.01 wt % to 15 wt %, preferably in the range of 0.1 wt % to 15 wt %, preferably in the range of 0.5 wt % to 10 wt %. However, without departing from the scope of the present invention, it may be necessary to deviate from the above amounts in individual cases or for specific applications.

[0079] According to a specific embodiment of the present invention, if according to synthetic route (A), the reaction is carried out in the presence of an enzyme as a catalyst, the pressure range applied can also vary within a wide range. In particular, if the reaction is carried out in the presence of an enzyme as a catalyst, the reaction can be carried out under a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, even more preferably about 1 bar.

[0080] According to an alternative embodiment of the present invention, the reaction according to the synthesis route (A) can also be carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst.

[0081] According to this alternative embodiment of the invention, according to synthesis route (A), the reaction is carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, which catalyst can be chosen in particular from (i) basic catalysts, in particular alkali metal or alkaline earth metal hydroxides and alkali metal or alkaline earth metal alcoholates, such as NaOH, KOH, LiOH, Ca(OH)2, NaOMe, KOMe and sodium tert-butoxide, (ii) acidic catalysts, in particular inorganic acids and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) Lewis acids, in particular Lewis acids based on titanium, tin, zinc and aluminum compounds, such as titanium tetrabutyrate, stannic acid, zinc acetate, aluminum trichloride and triisopropylaluminum, and (iv) heterogeneous catalysts, in particular based on mineral silicates, germanates, carbonates and aluminum oxides, such as zeolites, montmorillonites, mordenites, hydrotalcites and aluminum oxides, and combinations thereof.

[0082] According to the present embodiment, in particular, alkali or alkaline earth metal alcoholates can be used as catalysts according to synthesis route (A).

[0083] In particular, also according to the present embodiment, according to the synthesis route (A), it is preferred to recycle the catalyst based on a metal-containing and / or metal-based acidic or basic catalyst after the reaction.

[0084] If, according to a particular embodiment of the invention, the reaction according to synthesis route (A) is carried out in the presence of a metal-containing and / or metal-based acidic or basic catalyst, the temperature can vary within a wide range. In particular, in the presence of a metal-containing and / or metal-based acidic or basic catalyst, the temperature at which the reaction is carried out is in the range of 20° C. to 150° C., in particular in the range of 50° C. to 140° C., preferably in the range of 70° C. to 130° C., more preferably in the range of 80° C. to 125° C., even more preferably in the range of 100° C. to 120° C.

[0085] In addition, also according to this embodiment, according to the synthesis route (A), the catalyst (i.e., metal-containing and / or metal-based acidic or basic catalyst) can also be varied within a wide content range: for example, based on the total amount of starting compounds (Ia) and (II), the amount of catalyst based on metal-containing and / or metal-based acidic or basic catalyst is in the range of 0.01 wt% to 30 wt%, in particular in the range of 0.05 wt% to 15 wt%, preferably in the range of 0.1 wt% to 15 wt%, and also preferably in the range of 0.2 wt% to 10 wt%. However, without departing from the scope of the present invention, for specific applications or individual cases, the above amounts can be deviated from.

[0086] According to this embodiment of the invention, if, according to synthesis route (A), the reaction is carried out in the presence of an acidic or basic catalyst containing a metal and / or a metal group, the pressure range can be varied uniformly over a wide range: in particular, the reaction can be carried out in the presence of an acidic or basic catalyst containing a metal and / or a metal group under a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, more preferably about 1 bar.

[0087] Depending on the synthesis route (A), this can also vary within wide ranges with regard to the amounts of starting materials or starting compounds.

[0088] In view of process economy and optimization of the process, in particular with regard to minimization of by-products, according to synthesis route (A), it is advantageous that the compound of general formula (Ia) is used in a molar amount in the range of equimolar to 200 mol-% molar excess, in particular in the range of equimolar to 150 mol-% molar excess, preferably in the range of equimolar to 100 mol-% molar excess, based on the hydroxyl groups of fatty alcohol (II).

[0089] Likewise, with regard to process economy and optimization of the process course, in particular with regard to minimizing by-products, according to synthesis route (A), it is advantageous that the compound of the general formula (Ia) and the fatty alcohol (II) are used in a molar ratio of compound of the general formula (I) / polyol (II) in the range of 1:1 to 10:1, in particular in the range of 2:1 to 8:1, preferably in the range of 3:1 to 6:1.

[0090] According to a preferred embodiment of the method of the present invention, according to the synthetic route (A), preferably according to the synthetic route (A), at least one compound of the general formula (Ia') is reacted with a compound selected from C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - reacting at least one fatty alcohol (II) of a fatty alcohol;

[0091] CH3-CH(OH)-CH2-C(O)OC2H5 (Ia')

[0092] Thus, as reaction product (III), C of 3-hydroxybutyric acid is obtained. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - Fatty alcohol esters.

[0093] In the process of the invention, according to synthesis route (A), during the reaction, compounds according to the general formula (IVa) are simultaneously formed.

[0094] R 1 -OH (IVa)

[0095] In the general formula (IVa), the group R 1 Represents hydrogen or C1-C4-alkyl, in particular C1-C4-alkyl, preferably methyl or ethyl, more preferably ethyl. In particular, it is preferred in this case that according to synthesis route (A), the compound according to general formula (IVa) is extracted from the reaction, in particular continuously extracted, in particular preferably continuously removed by distillation.

[0096] Synthesis route (B)

[0097] The following is a review of the synthetic route (B) involved in the process of the present invention.

[0098] According to a particular embodiment of the present invention, according to the synthesis route (B), the compound of general formula (Ib) can be used in racemic form or in the form of (R)-enantiomers. The (R)-configuration refers to the two chiral carbon atoms of the compound of general formula (Ib), i.e. the carbon atoms marked with "*" in the following compound of general formula (Ib), each of these chiral centers corresponding to the corresponding C atom at the 3-position of 3-hydroxybutyric acid:

[0099] CH3-C*H(OR 2 )-CH2-C(O)-OC(O)-CH2-C*H(OR 2 )-CH3 (Ib).

[0100] In particular, it is preferred according to the method of the present invention that, according to the synthesis route (B) in the general formula (Ib), the group R 2 Represents the group -C(O)-CH3 (acetyl) and / or according to synthesis route (B), as compound of general formula (Ib), a compound of formula CH3-CH(OAc)-CH2-C(O)-OC(O)-CH2-CH(OAc)-CH3 is used, in which the group Ac represents acetyl.

[0101] Especially, in the inventive method, according to synthetic route (B), reaction is carried out in the absence of solvent and / or in the absence of any solvent. This means that the reaction is carried out with mass reaction or material reaction or so-called bulk reaction. This has the advantages that the reaction product obtained is not polluted by solvent, and after carrying out the method or reaction, there is no need to remove and dispose of or recycle solvent in an expensive and energy-consuming manner. Surprisingly, the method or reaction is still carried out with high conversion and yield, and at least substantially without significant by-product formation.

[0102] According to a particular embodiment of the process of the invention, according to synthesis route (B), the reaction can be carried out in particular autocatalytically or in the presence of a catalyst, in particular an inorganic acid. However, preferably, according to synthesis route (B), the reaction is carried out in an autocatalytic manner.

[0103] If the reaction according to synthesis route (B) is carried out in the presence of a catalyst, preferably according to synthesis route (B), the reaction is carried out in the presence of an inorganic acid. In particular, according to this embodiment, according to synthesis route (B), the catalyst and / or the inorganic acid can be selected from sulfuric acid, halogen acid, phosphoric acid and a combination thereof.

[0104] Within the scope of the production process of the invention according to synthesis route (B), it is preferred that, according to synthesis route (B), the temperature at which the reaction is carried out is in the range of 20°C to 150°C, in particular in the range of 50°C to 140°C, preferably in the range of 60°C to 130°C, more preferably in the range of 70°C to 125°C, still more preferably in the range of 75°C to 110°C.

[0105] Furthermore, within the scope of the production process according to the invention, it is preferred that, according to synthesis route (B), the reaction is carried out under pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, even more preferably at about 1 bar.

[0106] As regards the amount of starting materials or starting compounds, this can also vary within wide ranges depending on the synthesis route (B).

[0107] In view of process economy and optimization of the process course, in particular with regard to minimization of by-products, it is advantageous that, according to synthesis route (B), the compound of general formula (Ib) is used in a molar amount in the range of equimolar to 200 mol-% molar excess, in particular in the range of equimolar to 150 mol-% molar excess, preferably in the range of equimolar to 100 mol-% molar excess, based on the hydroxyl groups of fatty alcohol (II).

[0108] Likewise, with regard to process economy and optimization of the process course, in particular with regard to minimizing by-products, it is advantageous that, according to synthesis route (B), the compound of the general formula (Ib) and fatty alcohol (II) are used in a molar ratio of compound of the general formula (Ib) / fatty alcohol (II) in the range of 1:1 to 10:1, in particular in the range of 2:1 to 8:1, preferably in the range of 3:1 to 6:1.

[0109] According to a preferred embodiment of the method of the present invention according to the synthetic route (B), preferably according to the synthetic route (B), at least one compound of the general formula (Ib') is reacted with a compound selected from C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - reaction of at least one fatty alcohol (II) of a fatty alcohol followed by hydrolysis of the acyl group;

[0110] CH3-CH(OAc)-CH2-C(O)-OC(O)-CH2-CH(OAc)-CH3 (Ib')

[0111] Wherein, in the general formula (Ib'), the group Ac represents an acetyl group,

[0112] Thus, as reaction product (III), C of 3-hydroxybutyric acid is obtained. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - Fatty alcohol esters.

[0113] In the process of the invention, according to synthesis route (B), during the reaction, a compound according to the general formula (IVb) is simultaneously formed.

[0114] CH3-CH(OR 2 )-CH2-C(O)-OH (IVb)

[0115] In the general formula (IVb), the group R 2 represents an acyl group selected from -C(O)-CH3 (acetyl) or -C(O)-C2H5 (propionyl), preferably -C(O)-CH3 (acetyl). In particular, it is preferred in this case that, according to synthesis route (B), after the reaction has taken place, the compound according to general formula (IVb) is extracted, in particular removed by distillation.

[0116] Within the scope of the process according to the invention, the reaction of at least one compound of the general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above is followed by the hydrolysis of the acyl groups formed during the reaction according to synthesis route (B); thus, this reaction also leads to the acylation, in particular acetylation or propionylation, of the hydroxyl function located in the 3-position of 3-hydroxybutyric acid (i.e. the hydrogen atom of the hydroxyl function located in the 3-position of 3-hydroxybutyric acid is replaced by an acyl group, in particular by an acetyl group-C(O)-CH3 or a propionyl group-C(O)-C2H5). The hydrolysis of the acyl groups according to synthesis route (B) ultimately results in a reaction product (III) which does not contain acyl groups. For this purpose, according to the invention, according to synthesis route (B), at least one compound of the general formula (Ib) as defined above is reacted with at least one fatty alcohol (II) as defined above, followed by the selective or partial hydrolysis of the acyl groups present in the reaction product (=reaction intermediate) after the reaction has taken place. Thus, a reaction product (III) according to the following definition can be obtained, wherein the acyl group is replaced by a hydrogen atom during the hydrolysis and thus comprises a free hydroxyl function (i.e. in the position of the reaction product (III), which returns to the 3-position of the 3-hydroxybutyric acid moiety in the reaction product (III)).

[0117] In particular, according to the synthesis route (B), the hydrolysis of acyl groups, especially acetyl groups, is preferably carried out in the presence of a catalyst, preferably an enzyme. This ensures the selective or partial hydrolysis of acyl groups, especially under mild and economical conditions, preferably avoiding the formation of by-products.

[0118] In particular, according to synthesis route (B), it is preferred that the enzyme used for hydrolyzing acyl groups, in particular acetyl groups, can be selected from synthetases (ligases), catalases, esterases, lipases and combinations thereof. According to the present invention, synthetases (synonymous ligases) are in particular enzymes from the class of ligases; ligases are enzymes that catalyze the joining of two or more molecules by covalent bonds. Catalase in the sense of the present invention is in particular an enzyme that is able to convert hydrogen peroxide into oxygen and water. The term esterase refers in particular to enzymes that are able to hydrolyze esters into alcohols and acids (saponification); these are therefore in particular hydrolases, wherein lipolytic esterases are also referred to as lipases. In the sense of the present invention, lipases are in particular enzymes that are able to separate free fatty acids from lipids such as glycerides (lipolysis).

[0119] In particular, according to synthesis route (B), the enzyme used to hydrolyze acyl groups, especially acetyl groups, can be derived from Candida antarctica, Mucor miehei (Mucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus dei and Pseudomonas, and combinations thereof, preferably from Candida antarctica, Mucor miehei (Mucor miehei) and Thermomyces lanuginosus.

[0120] In particular, according to synthesis route (B), the enzyme for hydrolyzing acyl groups, in particular acetyl groups, can be used in an immobilized form, in particular on a carrier, preferably on a polymer carrier, preferably on a polymer organic carrier, more preferably having hydrophobicity, even more preferably on a poly(meth)acrylic resin-based carrier.

[0121] In particular, according to synthesis route (B), the enzyme for hydrolyzing acyl groups, especially acetyl groups, can be used in an amount in the range of 0.001 wt % to 20 wt %, especially in the range of 0.01 wt % to 15 wt %, preferably in the range of 0.1 wt % to 15 wt %, preferably in the range of 0.5 wt % to 10 wt %, based on the total amount of the compound to be hydrolyzed.

[0122] According to this embodiment, it is preferred that the enzyme used for hydrolyzing acyl groups, in particular acetyl groups, according to synthesis route (B) is recycled after the hydrolysis.

[0123] According to the synthesis route (B), the temperature at which the hydrolysis of the acyl group, in particular the acetyl group, is carried out can be in the range of 10°C to 80°C, in particular in the range of 20°C to 80°C, preferably in the range of 25°C to 75°C, more preferably in the range of 45°C to 75°C, still more preferably in the range of 50°C to 70°C.

[0124] According to synthesis route (B), the pressure during the hydrolysis of acyl groups, especially acetyl groups, can be 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, more preferably about 1 bar.

[0125] Typically, according to synthesis route (B), the hydrolysis of the acyl group, in particular the acetyl group, is carried out in the presence of water.

[0126] According to this embodiment of the process of the invention, commercially available enzymes having the above definition can be used as the enzymes described above according to synthesis route (B) (e.g. CALB enzymes on polymer supports derived from Candida antarctica, e.g. CALB enzymes from Sigma Aldrich or Merck). 435, or from Strem Chemicals, Inc. 435).

[0127] As described above, according to the synthesis route (B), the compound of the general formula (Ib) as defined above is used as a reactant. The compound of the general formula (Ib) as defined above is easily or conveniently available.

[0128] As far as the compounds of the general formula (Ib) defined above are concerned and used in the process according to the invention according to synthesis route (B), they can be obtained by reacting a carboxylic acid anhydride of the general formula (V) with 3-hydroxybutyric acid,

[0129] R 2 -OR 2 (V)

[0130] Among them, the group R 2 has the meaning defined above, in particular acetic anhydride or propionic anhydride, preferably acetic anhydride.

[0131] In particular, the reaction of the carboxylic anhydride of general formula (V) with 3-hydroxybutyric acid can be carried out according to the following reaction equation,

[0132]

[0133] Among them, the group R 2 has the meaning defined above.

[0134] According to a specific embodiment, the reaction of acetic anhydride and 3-hydroxybutyric acid may occur according to the following reaction equation,

[0135]

[0136] Therein, the group Ac represents an acetyl group.

[0137] The temperature for the reaction of the carboxylic anhydride of the general formula (V) as defined above with 3-hydroxybutyric acid can vary within a wide range. In particular, the temperature at which the reaction of the carboxylic anhydride of the general formula (V) as defined above with 3-hydroxybutyric acid is carried out can be in the range of 60 to 150° C., in particular in the range of 70 to 120° C., preferably in the range of 80 to 100° C.

[0138] The pressure for the reaction of the carboxylic anhydride of the general formula (V) defined above with 3-hydroxybutyric acid can vary uniformly within a wide range. In particular, the reaction of the carboxylic anhydride of the general formula (V) as defined above with 3-hydroxybutyric acid can be carried out under a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, even more preferably about 1 bar.

[0139] According to a particular embodiment of the process of the invention according to synthesis route (B), the invention relates to a process for producing fatty alcohol esters of 3-hydroxybutyric acid (β-hydroxybutyric acid, BHB or 3-BHB) as defined above,

[0140] Wherein, according to the synthetic route (B),

[0141] (a) in a first process step (a), a carboxylic anhydride of the general formula (V) as defined above, in particular acetic anhydride or propionic anhydride, preferably acetic anhydride, is reacted with 3-hydroxybutyric acid to obtain a compound of the general formula (Ib) as defined above,

[0142] R 2 -OR 2 (V)

[0143] Where R 2 has the meaning defined above; and

[0144] (b) in a second process step (b), the compound of general formula (Ib) thus obtained as defined above is reacted with a compound selected from C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - at least one fatty alcohol (II) of the fatty alcohol is reacted; and then

[0145] (c) in a third process step (c), the acyl group is hydrolyzed,

[0146] Thus, as reaction product (III), C of 3-hydroxybutyric acid is obtained. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - Fatty alcohol esters.

[0147] As described above with respect to synthesis route (B), the reaction of at least one compound of the general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above according to synthesis route (B) also leads to the acylation, in particular acetylation or propionylation, of the hydroxyl function located at the 3-position of 3-hydroxybutyric acid (i.e. the hydrogen atom of the hydroxyl function located at the 3-position of 3-hydroxybutyric acid is replaced by an acyl group, in particular acetyl-C(O)-CH3 or propionyl-C(O)-C2H5). The reaction product (=reaction intermediate (IIIa)) obtained during the reaction of at least one compound of the general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above can be separated or isolated without subsequent hydrolysis of the acyl group.

[0148] Because, as mentioned above, the applicant unexpectedly discovered that the reaction intermediate (IIIa) formed according to the synthetic route (B) before the hydrolysis of the acyl group (i.e., the fatty alcohol ester of acylated 3-hydroxybutyric acid or the fatty alcohol ester of 3-acyloxybutyric acid) is an effective, physiologically compatible precursor and / or metabolite of 3-hydroxybutyric acid or its salt, and because of its physiological compatibility, it can also be used in large quantities in medicine or clinic; therefore, these reaction intermediates also represent physiologically and pharmacologically relevant alternatives to free 3-hydroxybutyric acid or its salt.

[0149] According to a particular embodiment of the synthetic route (B), before the hydrolysis of the acyl group, in particular the acetyl group, as a reaction intermediate (IIIa), the C of the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) can be obtained. 10 -C 30 - fatty alcohol esters, especially acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) 10 -C 24 - fatty alcohol esters, preferably linear or branched, saturated or monounsaturated or polyunsaturated fatty alcohol esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) 10 -C 30 - fatty alcohol esters, preferably linear or branched, saturated or mono- or polyunsaturated fatty alcohols of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) 10 -C 24 - Fatty alcohol esters.

[0150] According to another specific embodiment, according to the synthetic route (B), before the hydrolysis of the acyl group, in particular the acetyl group, as a reaction intermediate (IIIa), a compound derived from C 10 -C 30 - acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylates of fatty alcohols, especially those derived from C 10 -C 24- acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols, preferably derived from linear or branched C 10 -C 24 - carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric alcohols and preferably primary C 10 -C 30 Acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric alcohols and preferably primary C 10 -C 24 Acylation of fatty alcohols Carboxylic acid esters of 3-hydroxybutyric acid (3-acyloxybutyric acid).

[0151] In particular, in this paper, C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - fatty alcohol, which can be selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearl alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosyl alcohol (wood wax alcohol), 1-hexacosyl alcohol (wax alcohol), 1-octacosanol (montanol), 1-triacontol (melissa alcohol), cis-9-hexadecene-1-ol (palmitoleyl alcohol), cis-9-octadecene-1-ol (oleyl alcohol), trans-9-octadecene-1-ol (antioleyl alcohol), cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol (linoleyl alcohol), 6,9,12-octadecatriene-1-ol (γ-linoleyl alcohol) and combinations thereof, preferably cis-9-octadecene-1-ol (oleyl alcohol).

[0152] According to the invention, it is preferred in this case that the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is acetylated 3-hydroxybutyric acid (3-acetoxybutyric acid).

[0153] According to another specific embodiment of the synthetic route (B), before the hydrolysis of the acyl group, in particular the acetyl group, as a reaction intermediate (IIIa), an acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid ester can be obtained, which is derived from a linear, saturated or mono- or polyunsaturated aliphatic monoprimary C 10 -C 24 Fatty alcohol.

[0154] Finally, according to another specific embodiment of the synthetic route (B), before the hydrolysis of the acyl group, in particular the acetyl group, as a reaction intermediate (IIIa), an acylated fatty alcohol ester of 3-hydroxybutyric acid (3-acyloxybutyric acid) of the general formula (IIIa) can be obtained.

[0155] CH3-CH(OR 2 )-CH2-C(O)OR 3 (IIIa)

[0156] Wherein, in the general formula (IIIa),

[0157] ·R 2 represents an acyl group selected from -C(O)-CH3(acetyl) or -C(O)-C2H5(propionyl), preferably -C(O)-CH3(acetyl),

[0158] ·R 3 Indicates linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl, preferably C 10 -C 24 -alkyl.

[0159] In particular, the group R in the general formula (IIIa) 3 It may represent 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecanyl (perfume), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melisyl), cis-9-hexadecen-1-yl (palmitoleyl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (antioleyl), cis-11-octadecen-1-yl, cis, cis-9,12-octadecadien-1-yl (linoleyl) or 6,9,12-octadecatriene-1-yl (γ-linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

[0160] General further description of the process according to the invention, in particular according to synthesis route (A) and synthesis route (B)

[0161] All the following descriptions relate to the process of the present invention as a whole or similarly, that is, both the synthetic route (A) and the synthetic route (B) of the process of the present invention.

[0162] According to the synthetic route (A) and the synthetic route (B) of the method of the present invention, using a compound selected from C 10 -C 30 Fatty alcohols, especially C 10 -C 24 The fatty alcohol (II) of the fatty alcohol is used as a reactant.

[0163] According to a specific embodiment of the method of the present invention, it can be particularly specified that the fatty alcohol (II) used in the method of the present invention corresponds to the general formula (II'),

[0164] R 3 -OH (II')

[0165] Among them, the group R 3 Indicates linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl group, preferably C 10 -C 24 - alkyl groups, in particular in which the hydroxyl function (OH function) is in primary position and / or terminal.

[0166] In particular, it is preferred in the context of the present invention that, in the general formula (II'), the radical R 3 Indicates linear, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 24 - Alkyl groups; in particular hydroxyl functions (OH functions) in primary and / or terminal positions.

[0167] In particular, it is further preferred in the context of the present invention that, in the general formula (II'), the radical R 3 The term "decyl" refers to 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecyl (perfume), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melisyl), cis-9-hexadecen-1-yl (palmitoleyl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (antioleyl), cis-11-octadecen-1-yl, cis, cis-9,12-octadecadien-1-yl (linoleyl) or 6,9,12-octadecatriene-1-yl (γ-linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

[0168] In particular, the fatty alcohol (II) that can be used in the process of the present invention can be selected from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic C 10 -C 30 - fatty alcohols, especially C 10 -≤C 24 Fatty alcohols preferably have primary hydroxyl groups and / or terminal hydroxyl functions (OH functions).

[0169] According to a particular embodiment of the process of the invention, the fatty alcohol (II) may be selected from linear, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 30 Fatty alcohols, especially linear, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 24 Fatty alcohol.

[0170] According to another specific embodiment of the method of the present invention, the fatty alcohol (II) can be selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearl alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosyl alcohol (wood wax alcohol), 1-hexacosyl alcohol (wax alcohol), 1-octacosanol (montanol), 1-triacontol (melissa alcohol), cis-9-hexadecene-1-ol (palmitoleyl alcohol), cis-9-octadecene-1-ol (oleyl alcohol), trans-9-octadecene-1-ol (antioleyl alcohol), cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol (linoleyl alcohol), 6,9,12-octadecatriene-1-ol (γ-linoleyl alcohol) and combinations thereof, preferably cis-9-octadecene-1-ol (oleyl alcohol).

[0171] The above-mentioned fatty alcohol (II) is a commercially available chemical product or can be easily obtained elsewhere.

[0172] As regards the reaction products obtainable in the process according to the invention, as reaction product (III) of the process according to the invention (according to synthesis route (A) and according to synthesis route (B)), in each case C of 3-hydroxybutyric acid is obtained, as described above. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - Fatty alcohol esters.

[0173] In particular, during the process of the invention, as reaction product (III), C of 3-hydroxybutyric acid can be obtained. 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - fatty alcohol esters, preferably linear or branched, saturated, monounsaturated or polyunsaturated fatty alcohol esters of 3-hydroxybutyric acid 10 -C 30 - fatty alcohol esters, preferably linear or branched, saturated, monounsaturated or polyunsaturated fatty alcohol esters of 3-hydroxybutyric acid 10 -C 24 - Fatty alcohol esters.

[0174] In particular, during the process of the invention, as reaction product (III) a compound derived from C 10 -C 30 - 3-hydroxybutyric acid esters of fatty alcohols, especially those derived from C 10 -C 24 - 3-hydroxybutyric acid carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C 10 -C 30 3-Hydroxybutyric acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 24 - 3-Hydroxybutyric acid esters of fatty alcohols.

[0175] Within the scope of the method of the present invention, C 10 -C 30 - fatty alcohols, especially C 10 -C 24 - fatty alcohol, which can be selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearl alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosyl alcohol (wood wax alcohol), 1-hexacosyl alcohol (wax alcohol), 1-octacosanol (montanol), 1-triacontol (melissa alcohol), cis-9-hexadecene-1-ol (palmitoleyl alcohol), cis-9-octadecene-1-ol (oleyl alcohol), trans-9-octadecene-1-ol (antioleyl alcohol), cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol (linoleyl alcohol), 6,9,12-octadecatriene-1-ol (γ-linoleyl alcohol) and combinations thereof, preferably cis-9-octadecene-1-ol (oleyl alcohol).

[0176] According to a particular embodiment of the process of the invention, as reaction product (III), a fatty alcohol ester of 3-hydroxybutyric acid of the general formula (III') can be obtained.

[0177] CH3-CH(OH)-CH2-C(O)OR 3 (III')

[0178] Among them, the group R 3 Indicates linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl group, preferably C 10 -C 24 -alkyl group.

[0179] According to another specific embodiment of the method of the present invention, as the reaction product (III), a 3-hydroxybutyric acid fatty alcohol ester of the above general formula (III') can be obtained, wherein in the general formula (III'), the group R 3 Indicates linear, saturated or monounsaturated or polyunsaturated C 10 -C 24 Aliphatic alkyl.

[0180] According to another specific embodiment of the method of the present invention, as the reaction product (III), a fatty alcohol ester of 3-hydroxybutyric acid of the general formula (III') can be obtained, wherein in the general formula (III'), the group R 3 It represents 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecanyl (perfumeryl), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melisyl), cis-9-hexadecene-1-yl (palmitoleyl), cis-9-octadecene-1-yl (oleyl), trans-9-octadecene-1-yl (antioleyl), cis-11-octadecene-1-yl, cis, cis-9,12-octadecadien-1-yl (linoleyl) or 6,9,12-octadecadien-1-yl (γ-linoleyl), preferably cis-9-octadecene-1-yl (oleyl).

[0181] As mentioned above, the applicant has found, completely unexpectedly, that the above-mentioned reaction products (i.e. fatty alcohol esters of 3-hydroxybutyric acid) obtained according to the process of the present invention are effective as physiologically compatible precursors and / or metabolites of 3-hydroxybutyric acid or its salts and can also be used in large quantities in medicine or clinics because they are physiologically compatible; therefore, these reaction products represent physiologically and pharmacologically relevant alternatives to free 3-hydroxybutyric acid or its salts.

[0182] Within the scope of the production process of the invention, the reaction products and their formation, in particular the conversion and yield and the selectivity, can be controlled and / or adjusted by the reaction conditions, in particular by selecting the reaction temperature (conversion temperature) and / or selecting the reaction pressure (conversion pressure) and / or providing a catalyst and a selection of its type and / or amount and / or selecting the amount of starting compounds (reactants) and / or providing for the removal of by-products.

[0183] After the reaction, the reaction product obtained can be subjected to further customary or per se known purification or processing steps.

[0184] In this case, the reaction product obtained can be worked up or purified by distillation and / or chromatography after the reaction has taken place.

[0185] Furthermore, according to the invention, unreacted starting compounds (Ia) or (Ib) and / or (II) can be separated from the reaction product (III) and / or (in the case of synthesis route (B)) from the reaction intermediate (IIIa) and subsequently recycled. This method can improve process economy, especially in the case of large-scale or industrial implementation.

[0186] The preferred methods according to the invention according to the synthesis route (A) and according to the synthesis route (B) are illustrated by the following reactions or synthesis schemes (wherein the compounds (Ia), (Ib), (II), (III / III') and (IIIa) each have the meanings defined above, including the radicals R used therein 1 , R 2 and R 3 ):

[0187]

[0188] According to a second aspect of the present invention, another subject is a reaction product obtainable according to the process of the invention (as indicated above) or a reaction product according to the invention (i.e. C 10 -C 30 - fatty alcohol esters, especially C 10 -C 24 - fatty alcohol esters). In particular, the reaction product according to the invention can be obtained via synthesis route (A) and / or synthesis route (B).

[0189] In particular, according to this aspect of the invention, the object of the invention is a fatty alcohol ester of 3-hydroxybutyric acid, in particular the reaction product as defined above (i.e. a fatty alcohol ester obtainable according to the above-described inventive process or a fatty alcohol ester of the invention), wherein the fatty alcohol ester of 3-hydroxybutyric acid is C 10 -C 30 - fatty alcohol esters, especially 3-hydroxybutyric acid 10 -C 24 - fatty alcohol esters, preferably linear or branched, saturated or monounsaturated or polyunsaturated aliphatic C 10 -C 30 - fatty alcohol esters, preferably linear or branched, saturated or monounsaturated or polyunsaturated aliphatic C 10 -C 24 Fatty alcohol esters.

[0190] According to a particular embodiment of this aspect of the invention, the invention relates to a fatty alcohol ester of 3-hydroxybutyric acid, in particular as defined above, and in particular to a reaction product as defined above, wherein the fatty alcohol ester of 3-hydroxybutyric acid is derived from C 10 -C30 - 3-hydroxybutyric acid esters of fatty alcohols, especially those derived from C 10 -C 24 - 3-hydroxybutyric acid carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C 10 -C 30 3-Hydroxybutyric acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 24 -Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols.

[0191] In this context, the C from which the above-mentioned fatty alcohol ester of 3-hydroxybutyric acid according to the invention is derived 10 -C 30 - fatty alcohols, especially C 10 -C 24 - fatty alcohol, preferably selected from the group 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (perfumer alcohol), 1-octadecyl alcohol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosyl alcohol (lignocer alcohol), 1-hexacosyl alcohol (cerylanol), 1-octacosanol (montanol), 1-triacontol (melissa alcohol), cis-9-hexadecene-1-ol (palmitoleyl alcohol), cis-9-octadecene-1-ol (oleyl alcohol), trans-9-octadecene-1-ol (antioleyl alcohol), cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol (linoleyl alcohol), 6,9,12-octadecatriene-1-ol (γ-linoleyl alcohol) and combinations thereof, preferably cis-9-octadecene-1-ol (oleyl alcohol).

[0192] According to another embodiment of this aspect of the invention, the invention relates to a fatty alcohol ester of 3-hydroxybutyric acid, in particular as defined above, in particular the reaction product as defined above, wherein the fatty alcohol ester of 3-hydroxybutyric acid corresponds to the general formula (III'),

[0193] CH3-CH(OH)-CH2-C(O)OR 3 (III')

[0194] Among them, the group R 3 Indicates linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl group, preferably C 10 -C 24 -alkyl group.

[0195] According to the invention, it is particularly preferred in this context that, in the general formula (III'), the radical R3 Indicates linear, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 24 -alkyl group.

[0196] According to the invention, in this context it is likewise particularly preferred that, in the general formula (III'), the radical R 3 The term "decyl" refers to 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecyl (perfume), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melisyl), cis-9-hexadecen-1-yl (palmitoleyl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (antioleyl), cis-11-octadecen-1-yl, cis, cis-9,12-octadecadien-1-yl (linoleyl) or 6,9,12-octadecatriene-1-yl (γ-linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

[0197] As mentioned above, the applicant has discovered, completely unexpectedly, that the reaction intermediate formed prior to the acyl hydrolysis according to synthesis route (B) (i.e. the fatty alcohol ester of acylated 3-hydroxybutyric acid or synonymously the fatty alcohol ester of 3-acyloxybutyric acid) is effective as a physiologically compatible precursor and / or metabolite of 3-hydroxybutyric acid or its salts and, due to its physiological compatibility, can also be used in large quantities in medicine or clinics; therefore, this reaction intermediate also represents a physiologically and pharmacologically relevant alternative to free 3-hydroxybutyric acid or its salts.

[0198] Therefore, according to a second aspect of the present invention, the present invention also aims at reaction intermediates according to specific embodiments, in particular (chemical) products, in particular reaction intermediates (IIIa), preferably acylated fatty alcohol esters of 3-hydroxybutyric acid (3-acyloxybutyric acid), which can be obtained according to the process defined above, according to synthesis route (B) before hydrolysis of the acyl group.

[0199] According to this embodiment, the object of the present invention is in particular the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid), in particular the reaction intermediate as defined above, wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is the C 10 -C 30 - fatty alcohol esters, especially acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) 10 -C 24 - fatty alcohol esters, preferably linear or branched C acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)10 -C 30 - saturated or monounsaturated or polyunsaturated aliphatic fatty alcohol esters, preferably linear or branched, saturated or monounsaturated or polyunsaturated C 10 -C 24 - Aliphatic fatty alcohol esters.

[0200] In particular, according to this particular embodiment, the present invention relates to acylated fatty alcohol esters of 3-hydroxybutyric acid (3-acyloxybutyric acid), in particular as defined above, in particular as reaction intermediates defined above, wherein the acylated fatty alcohol esters of 3-hydroxybutyric acid (3-acyloxybutyric acid) are derived from C 10 -C 30 - acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylates of fatty alcohols, especially those derived from C 10 -C 24 - acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 30 Acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C 10 -C 24 Acylation of fatty alcohols Carboxylic acid esters of 3-hydroxybutyric acid (3-acyloxybutyric acid).

[0201] In this context, it is particularly preferred according to the invention that the above-mentioned fatty alcohol esters of acylated 3-hydroxybutyric acid according to the invention are derived from C 10 -C 30 Fatty alcohols, especially C 10 -C 24 The fatty alcohol is selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearl alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosyl alcohol (wood wax alcohol), 1-hexacosyl alcohol (wax alcohol), 1-octacosanol (montanol), 1-triacontol (melissa alcohol), cis-9-hexadecene-1-ol (palmitoleyl alcohol), cis-9-octadecene-1-ol (oleyl alcohol), trans-9-octadecene-1-ol (antioleyl alcohol), cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol (linoleyl alcohol), 6,9,12-octadecatriene-1-ol (γ-linoleyl alcohol) and combinations thereof, preferably cis-9-octadecene-1-ol (oleyl alcohol).

[0202] According to the invention, it is preferred in this case that the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is acetylated 3-hydroxybutyric acid (3-acetoxybutyric acid).

[0203] In particular, according to this particular embodiment, the present invention also targets acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol esters, in particular as defined above, in particular as defined above reaction intermediates, wherein the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester is derived from a linear, saturated or mono- or polyunsaturated aliphatic, mono-primary C 10 -C 24 Acylation of fatty alcohols, carboxylates of 3-hydroxybutyric acid (3-acyloxybutyric acid).

[0204] Finally, according to this embodiment, the present invention also relates to acylated fatty alcohol esters of 3-hydroxybutyric acid (3-acyloxybutyric acid), in particular as defined above, in particular as reaction intermediates defined above, wherein the acylated fatty alcohol ester of 3-hydroxybutyric acid (3-acyloxybutyric acid) is an acylated fatty alcohol ester of 3-hydroxybutyric acid (3-acyloxybutyric acid) of the general formula (IIIa),

[0205] CH3-CH(OR 2 )-CH2-C(O)OR 3 (IIIa)

[0206] Wherein, in the general formula (IIIa),

[0207] ·R 2 represents an acyl group selected from -C(O)-CH3(acetyl) or -C(O)-C2H5(propionyl), preferably -C(O)-CH3(acetyl),

[0208] ·R 3 Represents linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl, preferably C 10 -C 24 -alkyl.

[0209] In particular, the group R 3It may represent 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecanyl (perfume), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melisyl), cis-9-hexadecen-1-yl (palmitoleyl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (antioleyl), cis-11-octadecen-1-yl, cis, cis-9,12-octadecadien-1-yl (linoleyl) or 6,9,12-octadecatriene-1-yl (γ-linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

[0210] The reaction product obtainable by the process according to the invention or the reaction product according to the invention and / or the 3-hydroxybutyric acid fatty alcohol ester as defined above, or the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester as defined above (=intermediate reaction product before hydrolysis according to synthesis route (B)) obtainable by the production process according to the invention, or the 3-hydroxybutyric acid fatty alcohol ester according to the invention as defined above and the acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester as defined above, respectively, have a number of advantages and special features compared to the prior art:

[0211] As the applicant has surprisingly found, the reaction product obtainable by the process according to the invention or the reaction product according to the invention, respectively as defined above, and / or the fatty alcohol ester of 3-hydroxybutyric acid as defined above or the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, obtainable by the production process according to the invention, or the fatty alcohol ester of 3-hydroxybutyric acid as defined above, as well as the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention, as defined above, are suitable as precursors or metabolites of 3-hydroxybutyric acid or its salts, since, on the one hand, these compounds are converted physiologically, in particular in the gastrointestinal tract, to 3-hydroxybutyric acid or its salts, and, on the other hand, they simultaneously have good physiological compatibility or tolerability, in particular with regard to non-toxicity and acceptable organoleptic properties.

[0212] Furthermore, the reaction product obtainable by the process according to the invention or the reaction product according to the invention as defined above, and / or the fatty alcohol ester of 3-hydroxybutyric acid as defined above, and the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, obtainable by the production process according to the invention, or the fatty alcohol ester of 3-hydroxybutyric acid as defined above and the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above, respectively, are readily available or obtainable on a synthetic basis on a large scale, even on a commercial scale, and have the desired pharmaceutical or pharmacological qualities.

[0213] In addition, the reaction product obtainable according to the process of the invention or the reaction product of the invention and / or the fatty alcohol ester of 3-hydroxybutyric acid as defined above obtainable according to the production process of the invention as defined above, and the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, or the fatty alcohol ester of 3-hydroxybutyric acid of the invention as defined above, and the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of the invention as defined above, respectively, as defined above, can, if necessary, be provided in enantiomerically pure or enantiomerically enriched form.

[0214] The reaction product obtainable by the process according to the invention or the reaction product according to the invention, respectively as defined above, and / or the fatty alcohol esters of 3-hydroxybutyric acid as defined above, obtainable by the production process according to the invention, as well as the fatty alcohol esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, or the fatty alcohol esters of 3-hydroxybutyric acid according to the invention as defined above, as well as the fatty alcohol esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above, respectively, therefore represent effective pharmacological drug targets in the context of ketone body therapy in the human or animal body, respectively.

[0215] In the following, remaining aspects of the invention are explained in more detail.

[0216] According to a third aspect of the invention, another subject of the invention is a pharmaceutical composition, in particular a medicament (pharmaceutical) or a medicament, comprising a reaction product obtainable by the production process according to the invention or a reaction product according to the invention as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid as defined above obtainable by the production process according to the invention, and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid according to the invention as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above (=intermediate reaction product before hydrolysis according to synthesis route (B)).

[0217] In particular, according to this aspect of the invention, the invention relates to a pharmaceutical composition for the prophylactic and / or therapeutic treatment or for the prophylactic and / or therapeutic treatment of a disease of the human or animal body. This may particularly relate to diseases associated with disturbances in energy metabolism, in particular ketone body metabolism, such as, in particular, craniocerebral trauma, 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, fat metabolism diseases such as glucose transport defects (GLUT1 defects), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase defects, Huntington's disease, cancers such as T-cell lymphomas, astrocytomas and glioblastomas, HIV, rheumatic diseases such as rheumatoid arthritis and uric acid arthritis, gastrointestinal diseases such as chronic inflammatory bowel disease, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipid diseases, in particular Niemann-Pick disease, diabetes and the effects or side effects of chemotherapy.

[0218] Likewise, according to a fourth aspect of the invention, another subject of the invention is a reaction product obtainable by the production process according to the invention or a reaction product according to the invention as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, obtainable by the production process according to the invention, or a fatty alcohol ester of 3-hydroxybutyric acid according to the invention as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above, respectively, for the prophylactic and / or therapeutic treatment or for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with disorders of energy metabolism, in particular ketone body metabolism, such as in particular Head trauma, 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, fat metabolism diseases such as glucose transport deficiency (GLUT1 deficiency), VL-FAOD and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancer 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 sphingolipidosis, especially Niemann-Pick disease, diabetes and the effects or side effects of chemotherapy.

[0219] Likewise, according to a fifth aspect of the invention, another subject of the invention is a reaction product obtainable by the production process according to the invention or a reaction product according to the invention, respectively as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid as defined above, obtainable by the production process according to the invention, and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid according to the invention as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above, for the prophylactic and / or therapeutic treatment or for the production of a medicament for the prophylactic and / or therapeutic treatment of diseases of the human or animal body, in particular with disorders of energy metabolism, in particular ketone body metabolism. Diseases associated with dysregulation, such as, in particular, craniocerebral trauma, 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, fat metabolism diseases such as glucose transport deficiency (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, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipidosis, in particular Niemann-Pick disease, diabetes and the effects or side effects of chemotherapy.

[0220] Likewise, according to a sixth aspect of the invention, another subject of the invention is the use of a reaction product obtainable by the production process according to the invention or a reaction product according to the invention, respectively as defined above, or a fatty alcohol ester of 3-hydroxybutyric acid as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) as defined above obtainable by the production process according to the invention, or a fatty alcohol ester of 3-hydroxybutyric acid according to the invention as defined above and / or a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) according to the invention as defined above, for preventive and / or therapeutic treatment, or for the production of a medicament for preventive and / or therapeutic treatment or for application in catabolic states, such as starvation, dieting or low-carbohydrate nutrition.

[0221] Similarly, according to the seventh aspect of the present invention, another subject of the present invention is a food and / or food product comprising a reaction product obtainable by the production method of the present invention or a reaction product of the present invention as defined above, or a 3-hydroxybutyric acid fatty alcohol ester as defined above and / or an acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester as defined above obtainable by the production method of the present invention, or a 3-hydroxybutyric acid fatty alcohol ester of the present invention as defined above and / or an acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester of the present invention as defined above, respectively.

[0222] According to a particular embodiment, the food and / or food product may essentially be a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy snack, an appetite suppressant or a strength and / or endurance sports supplement.

[0223] Finally, according to an eighth aspect of the present invention, a further subject of the present invention is a reaction product as defined above, obtainable according to the production process of the present invention, or a reaction product of the present invention as defined above, or a 3-hydroxybutyric acid fatty alcohol ester as defined above and / or an acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester as defined above, obtainable according to the production process of the present invention, or a 3-hydroxybutyric acid fatty alcohol ester of the present invention as defined above and / or an acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) fatty alcohol ester of the present invention as defined above, in food and / or foods.

[0224] According to this aspect of the invention, the food and / or food product may in particular be a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy snack, an appetite suppressant or a strength and / or endurance sports supplement.

[0225] Those skilled in the art may easily recognize or implement further embodiments, modifications and variations of the present invention upon reading the specification without departing from the scope of the present invention.

[0226] The present invention is illustrated by the following examples, which are not intended to limit the invention in any way but are merely intended to illustrate exemplary and non-limiting implementations and configurations of the invention. Example

[0227] Abbreviations used

[0228] ·3-BHB-ethyl=3-hydroxybutyric acid ethyl ester

[0229] ·3-BHB-decyl=3-hydroxybutyrate decyl

[0230] ·3-BHB-Oleyl = 3-hydroxybutyrate oleyl

[0231] Dimer = dimer of 3-hydroxybutyric acid and / or ethyl 3-hydroxybutyrate (reaction by-product).

[0232] Production Example

[0233] The production process of the present invention is illustrated by the following examples. The general reaction scheme for this is shown and explained in the general description section.

[0234] Production of 3-BHB-decyl ester according to synthetic route (A)

[0235] In a 500 ml multi-necked flask with a fractionator (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate, 158 g of 1-decanol and 2.9 g of immobilized enzyme (CALB enzyme on a polymer support, derived from Candida antarctica, e.g., from Sigma Aldrich or Merck) are provided. 435 or from Strem Chemicals, Inc 435).

[0236] The reaction mixture was stirred at 70°C and vacuum (<500 mbar) for 7 hours. The enzyme was then filtered off and excess ethyl 3-hydroxybutyrate or excess 1-decanol was distilled off under vacuum. The resulting residue was steamed in high vacuum for 2 to 4 hours (steam temperature 160°C). Pure 3-BHB-decyl ester was obtained.

[0237] Production of 3-BHB-oleyl ester according to the synthetic route (A)

[0238] In a 500 ml multi-necked flask with a fractionator (partial condenser) and a distillation bridge, 132 g of (R) / (S)-ethyl 3-hydroxybutyrate, 270 g of oleyl alcohol (purity: 85%) and 4.0 g of immobilized enzyme (CALB enzyme on a polymer support, derived from Candida antarctica, e.g., from Sigma Aldrich or Merck) are provided. 435 or from Strem Chemicals, Inc 435).

[0239] The reaction mixture was stirred at 70°C and vacuum (<500 mbar) for 7 hours. To monitor the reaction, samples were taken after 0.5h, 1h, 2h, 3h, 4h, 5h and 7h and analyzed by GC. The enzyme was then filtered out and the product 3-BHB-oleyl ester was obtained by multiple distillations in vacuum. If necessary, the obtained residue was steamed in a high vacuum for 2 to 4 hours (steam temperature 160°C). Pure 3-BHB-oleyl ester was obtained.

[0240] surface:A conversion / time curve of 3-BHB-oleyl ester was prepared (50° C., 50-60 mbar, 24 h, 1 wt % enzyme).

[0241]

[0242] Further production of 3-BHB fatty alcohol esters according to synthetic route (A)

[0243] The enzymatic synthesis described above was also carried out with other fatty alcohols, namely cetyl alcohol, margaritol, stearyl alcohol, behenyl alcohol, myristyl alcohol, palmitoleyl alcohol and linoleyl alcohol. The corresponding 3-BHB fatty alcohol esters were obtained in each case as pure substances.

[0244] Further production of 3-BHB fatty alcohol esters according to synthetic route (A)

[0245] However, comparable results were obtained when repeating the previous experiment using sodium methoxide (NaOMe) as catalyst (1% by weight) instead of enzyme, 40 mol% excess of 3-BHB ethyl ester and temperature between 100 and 120° C. Purification and isolation were performed in the same manner.

[0246] Production of 3-BHB decyl ester according to synthetic route (B)

[0247] 1. Step: Synthesis of acetylated 3-BHB anhydride

[0248] In a 1000 ml multi-necked flask with a fractionator (partial condenser) and a distillation bridge, 25 g of (R) / (S)-3-hydroxybutyric acid in 95 g of acetic acid are provided. 90 g of acetic anhydride are added to the reaction mixture at 80° C. under a nitrogen atmosphere within one hour. The reaction mixture is further stirred at 80° C. for 4 to 5 hours. 3-Acetoxybutyric anhydride (=acetylated 3-hydroxybutyric anhydride) is formed.

[0249] 2. Step: Acetylation of 3-BHB anhydride and reaction with fatty alcohol

[0250] Then, 30 g of 1-decanol is added to the reaction mixture at 80° C. and stirred for 8 to 10 hours. The reaction product of the second stage is a fatty alcohol ester of 3-acetoxybutyric acid (i.e., in other words, a fatty alcohol ester of acetylated 3-hydroxybutyric acid) and an intermediate for producing the corresponding 3-BHB fatty alcohol ester, but it itself is also pharmaceutically suitable or effective for the same intended use.

[0251] The by-products formed (acetic acid in the first step and 3-acetoxybutyric acid in the second step) were distilled under vacuum (<50 mbar) at 100 to 120° C. to give pure fatty alcohol esters of 3-acetoxybutyric acid. Characterization was carried out by GC, GPC and GC-MS.

[0252] 3. Step: Enzymatic Hydrolysis of Acetyl Groups

[0253] The partial intermediate product of the second step (i.e. the fatty alcohol ester of 3-acetoxybutyric acid) is then subjected to hydrolysis of the acetyl group (partial or selective hydrolysis in the presence of an enzyme). For this purpose, the reaction product of the second step is reacted with an immobilized enzyme (CALB enzyme on a polymer support, derived from Candida antarctica, first preparation: from Sigma Aldrich or Merck 435, Second Formulation: from Strem Chemicals, Inc. 435) in an aqueous medium at 50°C for 8 hours. After enzyme separation and subsequent distillation purification, 3-hydroxybutyric acid fatty alcohol ester is obtained as the hydrolysis product, i.e. 3-hydroxybutyric acid decyl ester. It is characterized by GC, GPC and GC-MS.

[0254] The remainder of the intermediate was used in subsequent efficacy trials.

[0255] Further production of 3-BHB decyl ester according to synthetic route (B)

[0256] However, the previous experiment was repeated, and after the (R) / (S) 3-hydroxybutyric anhydride reaction, the by-product (acetic acid) formed in the first step was first removed by distillation at 100 to 120°C and vacuum (<50 mbar), to obtain pure 3-acetoxybutyric anhydride. Characterization was performed by GC, GPC and GC-MS.

[0257] Subsequently, pure 3-acetoxybutyric anhydride was reacted with 1-decanol, purified and analyzed (as described in previous experiments) to obtain pure 3-acetoxybutyric acid fatty alcohol esters.

[0258] The reaction product (ie, fatty alcohol ester of 3-acetoxybutyric acid) was then hydrolyzed as described in the previous experiment to obtain fatty alcohol ester of 3-hydroxybutyric acid, ie, decyl 3-hydroxybutyrate. Characterization was performed using GC, GPC, and GC-MS.

[0259] Production of 3-BHB oleyl ester according to the synthetic route (B)

[0260] 1. Step: Synthesis of acetylated 3-BHB anhydride

[0261] In a 1000 ml multi-necked flask with a fractionator (partial condenser) and a distillation bridge, 25 g of (R) / (S)-3-hydroxybutyric acid in 95 g of acetic acid are provided. 90 g of acetic anhydride are then added to the reaction mixture at 80° C. under a nitrogen atmosphere within one hour. The reaction mixture is further stirred at 80° C. for 4 to 5 hours. 3-Acetoxybutyric anhydride (=acetylated 3-hydroxybutyric anhydride) is formed.

[0262] 2. Step: Acetylation of 3-BHB anhydride and reaction with fatty alcohol

[0263] Then, 52 g of oleyl alcohol is added to the reaction mixture at 80° C. and stirred for 8 to 10 hours. The reaction product of the second step is a fatty alcohol ester of 3-acetoxybutyric acid (i.e., oleyl alcohol ester of acetylated 3-hydroxybutyric acid) and an intermediate for preparing the corresponding 3-BHB fatty alcohol ester, but it itself is also pharmaceutically suitable or effective for the same purpose.

[0264] The byproducts (acetic acid in the first step and 3-acetoxybutyric acid in the second step) were distilled under vacuum (<50 mbar) at 100 to 120° C. to give pure 3-acetoxybutyric acid fatty alcohol esters. Characterization was performed by GC, GPC and GC-MS.

[0265] 3. Step: Enzymatic Hydrolysis of Acetyl Groups

[0266] The partial intermediate from the second step (i.e. the oleyl ester of 3-acetoxybutyric acid) is subsequently subjected to hydrolysis of the acetyl group (partial or selective hydrolysis in the presence of an enzyme). For this purpose, the reaction product of the second step is reacted with an immobilized enzyme (CALB enzyme on a polymer support, derived from Candida antarctica, first preparation: 435, Second Formulation: from Strem Chemicals, Inc. 435) in an aqueous medium at 50°C for 8 hours. After enzyme separation and subsequent distillation purification, 3-hydroxybutyric acid fatty alcohol ester, i.e. 3-hydroxybutyric acid oleyl ester, is obtained as a hydrolyzate. It is characterized by GC, GPC and GC-MS.

[0267] The remainder of the intermediate was used for subsequent efficacy testing.

[0268] Further production of 3-BHB oleyl ester according to synthetic route (B)

[0269] The previous experiment was repeated, however, after the (R) / (S) 3-hydroxybutyric anhydride reaction, the by-product (acetic acid) formed in the first step was first removed by distillation at 100 to 120° C. under vacuum (<50 mbar) and pure 3-acetoxybutyric anhydride was obtained. Characterization was carried out by GC, GPC and GC-MS.

[0270] Subsequently, pure 3-acetoxybutyric anhydride was reacted with oleyl alcohol, purified and analyzed (as described in previous experiments) to give pure 3-acetoxybutyric acid fatty alcohol esters.

[0271] The reaction product (ie, oleyl ester of 3-acetoxybutyric acid) was subsequently hydrolyzed as described in previous experiments to give the oleyl ester of 3-hydroxybutyric acid, ie, oleyl 3-hydroxybutyrate. Characterization was performed using GC, GPC, and GC-MS.

[0272] Further production of 3-BHB fatty acid esters according to synthetic route (B)

[0273] However, each of the four experiments described above was repeated once in the presence of an acidic catalyst.

[0274] In a first series of preparations, the reaction of 1-decanol and oleyl alcohol was repeated in each case in the presence of sulfuric acid (H2SO4) as a catalyst at a temperature between 75 and 110° C. Comparable results were obtained. Purification, separation or fractionation and hydrolysis were carried out in the same manner.

[0275] In a second series of preparations, the reaction of 1-decanol and oleyl alcohol was repeated in each case in the presence of hydrochloric acid (HCl) as catalyst at temperatures between 75 and 110° C. Comparable results were obtained. Purification, separation or fractionation and hydrolysis were carried out in the same manner.

[0276] In a third series of preparations, the reaction of 1-decanol and oleyl alcohol was repeated at temperatures between 75 and 110° C. in the presence of phosphoric acid (H 3 PO 4 ) as a catalyst, respectively. Comparable results were obtained. The purification, separation or fractionation and hydrolysis were carried out in the same manner.

[0277] Further production of 3-BHB fatty alcohol esters according to synthetic route (B)

[0278] The above synthesis (autocatalytic and mineral acid catalytic) was also carried out accordingly for the other fatty alcohols (ie for cetyl alcohol, pearl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, palmitoleyl alcohol and linoleyl alcohol, respectively). The corresponding 3-BHB fatty alcohol esters were obtained in each case as pure substances.

[0279] Physiological application test: in vitro digestion test

[0280] Digestion test (splitting or cleavage test) of 3-BHB fatty alcohol ester (i.e. 3-hydroxybutyric acid fatty alcohol ester)

[0281] The cleavage experiment showed that the 3-BHB-PG(2) ester or a mixture thereof (including reaction by-products, such as dimers, etc.) prepared according to the present invention can be cleaved in the human gastrointestinal tract.

[0282] On the one hand, the test substance used is a purified 3-BHB fatty alcohol ester obtained by the method according to the present invention (i.e., obtained by the method according to synthesis route (A) and the method according to synthesis route (B)), and on the other hand, it is a pure acetylated 3-BHB (3-acetylbutyric acid) fatty alcohol ester obtained as a reaction intermediate by the method according to the present invention and according to synthesis route (B).

[0283] Fatty alcohol esters tested:

[0284] 3-BHB Decyl Ester

[0285] ·Acetylated 3-BHB decyl ester (3-acetoxybutyric acid decyl ester)

[0286] ·3-BHB ester

[0287] ·Acetylated 3-BHB oleyl ester (oleyl ester of 3-acetoxybutyric acid)

[0288] ·3-BHB hexadecyl ester

[0289] ·3-BHB Pearlescent Ester

[0290] 3-BHB Stearate

[0291] ·3-BHB Behenyl Ester

[0292] ·3-BHB Myricyl Ester

[0293] ·3-BHB Palm Oil Ester

[0294] ·3-BHB linoleate

[0295] Two culture media were investigated for lysis experiments under conditions similar to those in vivo:

[0296] FaSSGF, simulates gastric

[0297] FaSSIF, simulated intestinal tract

[0298] Both culture media were from the United Kingdom Ltd. In addition, porcine pancreas ( 40,000, Fa.Allergan).

[0299] In use and not using The results of the lysis experiment in FaSSGF or FaSSIF medium (both at 35°C, 24 hours) showed that the samples and not using This is mainly due to the low pH value of the culture medium (pH = 1.6). The conversion rate is low.

[0300] Further digestion experiment (cracking experiment) of 3-BHB fatty alcohol ester (i.e. fatty alcohol ester of 3-hydroxybutyric acid) of the present invention

[0301] Lysis experiment using trypsin

[0302] In each case, 2 g of fatty alcohol 3-hydroxybutyrate or its acetylated derivative prepared as described above (i.e. obtained by the process according to synthesis route (A) and by the process according to synthesis route (B)) were dissolved in 50 g of water and 0.5 g (1 wt %) of pancreatin was added. Pancreatin was commercially available as the product HYDROGEN® from Allergan. 40,000. The entire mixture is stirred on a hot plate at 50° C.; the course of the reaction is determined and monitored by continuously recording the acid value over time. The acid value increases during the observation period (3-BHB fatty alcohol ester or its acyl derivative is cleaved into free acid). The conversion rate / time course of the ester mixture according to the invention by pancreatic hydrolysis, including the increase in the acid value over time, proves that the isolated mixture is decomposed into free acid as expected. Appropriate analysis confirms this. The experiment proves that the fatty alcohol ester of 3-hydroxybutyric acid or its acetylated derivative according to the invention (i.e. obtained by the method according to synthesis route (A) and the method according to synthesis route (B)) is a suitable physiological precursor of 3-hydroxybutyric acid for the corresponding ketone body therapy.

[0303] The cleavage experiments described previously demonstrate that fatty alcohol esters of 3-hydroxybutyric acid or their acyl derivatives are efficient precursors or metabolites of free hydroxybutyric acid or its salts, in particular that they are present in a physiologically compatible form with respect to their intended effects.

Claims

1. A method for producing 3-hydroxybutyric acid fatty alcohol ester, At least one compound of formula (Ib) and selected from C 10 -C 30 - reaction of at least one fatty alcohol (II) of a fatty alcohol, followed by hydrolysis of the acyl group, CH3-CH(OR 2 )-CH2-C(O)-O-C(O)-CH2-CH(OR 2 )-CH3(Ib) in, In the general formula (Ib), the group R 2 represents an acyl group selected from an acetyl group of the formula -C(O)-CH3 or a propionyl group of the formula -C(O)-C2H5; Thus, as reaction product (III), in each case the C of 3-hydroxybutyric acid is obtained. 10 -C 30 - Fatty alcohol esters.

2. The method according to claim 1, in, The reaction is carried out in the absence of any solvent; and wherein the reaction is carried out in an autocatalytic manner or in the presence of a catalyst; and Therein, the compound of the general formula (Ib) and the fatty alcohol (II) are used in a molar ratio of the compound of the general formula (Ib) / the fatty alcohol (II) in the range of 1:1 to 10:

1.

3. The method according to claim 1 or 2, in, The hydrolysis of the acyl group is carried out in the presence of an enzyme as a catalyst; wherein the enzyme is selected from synthetase (ligase), catalase, esterase, lipase and combinations thereof; and wherein the enzyme is used in an immobilized form on a carrier; and wherein the enzyme is used in an amount ranging from 0.001 wt % to 20 wt % based on the total amount of the compound to be hydrolyzed; and Therein, the enzyme is recycled after the hydrolysis reaction.

4. The method according to claim 1, in, Fatty alcohol (II) corresponds to the general formula (II') R 3 -OH(II'), Among them, the group R 3 Indicates linear or branched, saturated, monounsaturated or polyunsaturated aliphatic C 10 -C 30 -alkyl group.

5. The method according to claim 4, in, Group R 3 represents 1-decyl, 1-dodecyl, 1-tetradecyl, 1-hexadecyl, 1-heptadecyl, 1-octadecyl, 1-eicosyl, 1-docosyl, 1-tetracosyl, 1-hexacosyl, 1-octacosyl, 1-triacontyl, cis-9-hexadecen-1-yl, cis-9-octadecen-1-yl, trans-9-octadecen-1-yl, cis-11-octadecen-1-yl, cis,cis-9,12-octadecadien-1-yl or 6,9,12-octadecadien-1-yl.

6. The method according to claim 1 or 2, in, Fatty alcohol (II) is selected from linear, saturated or monounsaturated or polyunsaturated, aliphatic monohydric and primary C 10 -C 30 fatty alcohols; and Wherein, the fatty alcohol (II) is selected from 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-heptadecanol, 1-octadecanol, 1-eicosanol, 1-docosapentaenoic acid, 1-tetracosanol, 1-hexacosanol, 1-octacosanol, 1-triacontol, cis-9-hexadecene-1-ol, cis-9-octadecene-1-ol, trans-9-octadecene-1-ol, cis-11-octadecene-1-ol, cis, cis-9,12-octadecadiene-1-ol, 6,9,12-octadecadiene-1-ol and combinations thereof.

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