阅读说明：本技术 用于生产羟基羧酸脂肪醇酯的方法 (Process for producing fatty alcohol esters of hydroxycarboxylic acids ) 是由 德克·洛赫曼 塞巴斯蒂安·雷耶 迈克尔·施特尔 于 2019-01-23 设计创作，主要内容包括：本发明涉及一种用于生产3-羟基丁酸及其酰化衍生物的脂肪醇酯的方法,以及由此获得的产物及其用途。(The present invention relates to a process for the production of fatty alcohol esters of 3-hydroxybutyric acid and its acylated derivatives, as well as the products thus obtained and their uses.)

1. A method for producing 3-hydroxybutyric acid (beta-hydroxybutyric acid, BHB or 3-BHB) fatty alcohol ester,

(A) wherein, according to (first) scheme (A), at least one compound of formula (Ia) is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols,

CH₃-CH(OH)-CH₂-C(O)OR¹(Ia)

wherein, in the general formula (Ia), the group R¹Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl;

or

(B) Wherein, according to (second, alternative (A)) scheme (B), at least one compound of formula (Ib) is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols, followed by acyl hydrolysis,

CH₃-CH(OR²)-CH₂-C(O)-O-C(O)-CH₂-CH(OR²)-CH₃(Ib)

whereinIn the general formula (Ib), the radical R²Represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group);

thus, as reaction product (III), in each case C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

2. The method of claim 1, wherein the first and second light sources are selected from the group consisting of,

wherein, according to the synthetic route (A), the compounds of the general formula (Ia) are used in racemic form or in the form of the (R) -enantiomer.

3. The method according to claim 1 or 2,

wherein, according to the synthesis scheme (A), in the general formula (I), the group R¹Represents ethyl, and/or

Wherein, according to scheme (A), as the compound of general formula (Ia), the compound of formula CH is used₃-CH(OH)-CH₂-C(O)OC₂H₅Ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate).

4. The method according to any one of claims 1 to 3,

wherein, according to scheme (a), the reaction is carried out without solvent and/or without any solvent; and/or

Wherein, according to scheme (a), the reaction is carried out in the presence of a catalyst, in particular an enzyme and/or a metal-and/or metal-based acidic or basic catalyst, preferably in the presence of an enzyme; in particular, wherein the catalyst is recycled after the reaction according to scheme (a).

5. The method according to any one of claims 1 to 4,

wherein, according to scheme (a), the reaction is carried out in the presence of an enzyme as catalyst;

in particular wherein, according to scheme (a), the enzyme is selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof; and/or

In particular wherein, according to scheme (a), the enzymes are preferably from the genera candida antarctica, trichoderma oryzae (rhizomucor miehei), thermomyces lanuginosus, candida rugosa, aspergillus oryzae, pseudomonas cepacia, pseudomonas fluorescens, rhizopus prodigiosus and pseudomonas, and combinations thereof, preferably from candida antarctica, trichoderma oryzae (rhizopus miehei) and thermomyces lanuginosus; and/or

In particular wherein, according to scheme (a), the enzyme is used in immobilized form, in particular immobilized on a support, preferably on a polymeric organic support, more preferably having hydrophobic properties, still more preferably on a support based on poly (meth) acrylic resins; and/or

In particular wherein, according to scheme (a), the enzyme is recycled after the reaction; and/or

In particular wherein, according to scheme (a), the reaction is carried out at a temperature in the range of from 10 ℃ to 80 ℃, in particular in the range of from 20 ℃ to 80 ℃, preferably in the range of from 25 ℃ to 75 ℃, more preferably in the range of from 45 ℃ to 75 ℃, still more preferably in the range of from 50 ℃ to 70 ℃ in the presence of an enzyme as catalyst; and/or

In particular wherein, according to scheme (a), the enzyme is used in an amount in the range of from 0.001 to 20 wt. -%, in particular in the range of from 0.01 to 15 wt. -%, preferably in the range of from 0.1 to 15 wt. -%, preferably in the range of from 0.5 to 10 wt. -%, based on the total amount of the starting compounds (Ia) and (II); and/or

In particular wherein, according to scheme (a), the reaction is carried out in the presence of an enzyme as catalyst under a pressure in the range of from 0.0001 bar to 10 bar, in particular in the range of from 0.001 bar to 5 bar, preferably in the range of from 0.01 bar to 2 bar, more preferably in the range of from 0.05 bar to 1 bar, even more preferably about 1 bar.

6. The method of any one of claims 1 to 4,

wherein, according to scheme (a), the reaction is carried out in the presence of an acidic or basic catalyst comprising a metal and/or a metal base;

in particular, wherein, according to scheme (A), the catalyst is selected 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)₂NaOMe, KOMe and sodium tert-butoxide, (ii) acidic catalysts, especially inorganic and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) lewis acids, especially 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, especially based on mineral silicates, germanates, carbonates and aluminas, such as zeolites, montmorillonites, mordenite, hydrotalcite and alumina, and combinations thereof; and/or

In particular wherein, according to scheme (a), an alkali or alkaline earth alcoholate is used as catalyst; and/or

In particular wherein, according to scheme (a), the catalyst is recovered after the reaction; and/or

In particular wherein, according to scheme (a), the reaction is carried out at a temperature in the range of from 20 ℃ to 150 ℃, in particular in the range of from 50 ℃ to 140 ℃, preferably in the range of from 70 ℃ to 130 ℃, more preferably in the range of from 80 ℃ to 125 ℃, still more preferably in the range of from 100 ℃ to 120 ℃, in the presence of an acidic or basic catalyst comprising a metal and/or a metal base; and/or

In particular wherein, according to scheme (a), the catalyst is used in an amount in the range of from 0.01 to 30 wt. -%, in particular in the range of from 0.05 to 15 wt. -%, preferably in the range of from 0.1 to 15 wt. -%, preferably in the range of from 0.2 to 10 wt. -%, based on the total amount of the starting compounds (Ia) and (II); and/or

In particular wherein, according to scheme (a), the reaction is carried out in the presence of an acidic or basic catalyst comprising a metal and/or metal base under a pressure in the range of from 0.0001 bar to 10 bar, in particular in the range of from 0.001 bar to 5 bar, preferably in the range of from 0.01 bar to 2 bar, more preferably in the range of from 0.05 bar to 1 bar, even more preferably about 1 bar.

7. The method of any one of claims 1 to 6,

wherein, according to scheme (A), the compound of formula (Ia) is used in a molar amount in the range of an equimolar amount to a molar excess of 200 mol-%, in particular in the range of an equimolar amount to a molar excess of 150 mol-%, preferably in the range of an equimolar amount to a molar excess of 100 mol-%, based on the hydroxyl groups of the fatty alcohol (II); and/or

Wherein, according to scheme (A), the compound of formula (Ia) and the fatty alcohol (II) are used in a molar ratio of compound of formula (Ia) to fatty alcohol (II) ranging from 1:1 to 10:1, in particular ranging from 2:1 to 8:1, preferably ranging from 3:1 to 6: 1.

8. The method according to any one of the preceding claims 1 to 7,

wherein, according to scheme (A), at least one compound of formula (Ia') is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols,

CH₃-CH(OH)-CH₂-C(O)OC₂H₅(Ia’)；

thus, as the reaction product (III), C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

9. The method according to any one of the preceding claims 1 to 8,

wherein, according to scheme (A), during the reaction, a compound of general formula (IVa) is formed simultaneously,

R¹-OH (IVa)

wherein, in the general formula (I)Va), the radical R¹Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl;

in particular, the compound of the formula (IVa) is extracted from the reaction according to the synthesis route (a), in particular continuously, in particular preferentially continuously removed by distillation.

10. The method of claim 1, wherein the first and second light sources are selected from the group consisting of,

wherein, according to the scheme (B), the compounds of general formula (Ib) are used in racemic form or in (R) -enantiomeric form.

11. The method according to claim 1 or 10,

wherein, according to scheme (B), in formula (Ib), the radical R²Represents a group-C (O) -CH₃(acetyl group); and/or

Wherein, according to scheme (B), as compounds of general formula (Ib) use is made of formula CH₃-CH(OAc)-CH₂-C(O)-O-C(O)-CH₂-CH(OAc)-CH₃Wherein the group Ac represents an acetyl group.

12. The method of any one of claims 1, 10 and 11,

wherein, according to scheme (B), the reaction is carried out without a solvent and/or without any solvent.

13. The method of any one of claims 1 and 10 to 12,

wherein, according to scheme (B), the reaction is carried out in an autocatalytic manner or in the presence of a catalyst, in particular a mineral acid, preferably in an autocatalytic manner.

14. The method of any one of claims 1 and 10 to 13,

wherein, according to scheme (B), the reaction is carried out in the presence of a catalyst, in particular an inorganic acid;

in particular wherein, according to scheme (B), the catalyst and/or the mineral acid is selected from the group consisting of sulfuric acid, hydrohalic acid, phosphoric acid and combinations thereof.

15. The method of any one of claims 1 and 10 to 14,

wherein, according to scheme (B), the reaction is carried out at a temperature in the range of from 20 ℃ to 150 ℃, in particular in the range of from 50 ℃ to 140 ℃, preferably in the range of from 60 ℃ to 130 ℃, more preferably in the range of from 70 ℃ to 125 ℃, still more preferably in the range of from 75 ℃ to 110 ℃; and/or

Wherein, according to scheme (B), the reaction is carried out at a pressure in the range of 0.0001 bar to 10 bar, in particular in the range of 0.001 bar to 5 bar, preferably in the range of 0.01 bar to 2 bar, more preferably in the range of 0.05 bar to 1 bar, even more preferably about 1 bar.

16. The method of any one of claims 1 and 10 to 15,

wherein, according to scheme (B), the compound of formula (Ib) is used in a molar amount in the range of an equimolar amount to a molar excess of 200 mol-%, in particular in the range of an equimolar amount to a molar excess of 150 mol-%, preferably in the range of an equimolar amount to a molar excess of 100 mol-%, based on the hydroxyl groups of fatty alcohol (II); and/or

Wherein, according to scheme (B), the compound of formula (Ib) and the fatty alcohol (II) are used in a molar ratio of compound of formula (Ib) to 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.

17. The method of any one of claims 1 and 10 to 16,

wherein, according to scheme (B), at least one compound of formula (Ib') is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols, followed by hydrolysis of the acyl group,

CH₃-CH(OAc)-CH₂-C(O)-O-C(O)-CH₂-CH(OAc)-CH₃ (Ib’)，

wherein, in formula (Ib'), the group Ac represents an acetyl group;

thus, as the reaction product (III), C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

18. The method of any one of claims 1 and 10 to 17,

wherein, according to scheme (B), during the reaction, a compound according to general formula (IVb) is formed simultaneously,

CH₃-CH(OR²)-CH₂-C(O)-OH (IVb)，

wherein, in the general formula (IVb), the group R²Represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group);

in particular, according to scheme (B), the compound of formula (IVb) is extracted after the reaction has taken place, in particular continuously, in particular preferably continuously removed by distillation.

19. The method of any one of claims 1 and 10 to 18,

wherein, according to scheme (B), the hydrolysis of acyl groups, in particular acetyl groups, is carried out in the presence of a catalyst, preferably an enzyme;

in particular wherein the enzyme is selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof; and/or

In particular wherein the enzyme is from the genera candida antarctica, trichoderma oryzae (rhizomucor miehei), thermomyces lanuginosus, candida rugosa, aspergillus oryzae, pseudomonas cepacia, pseudomonas fluorescens, rhizopus prodigiosus and pseudomonas, and combinations thereof, preferably from the genera candida antarctica, trichoderma oryzae (rhizopus miehei) and thermomyces lanuginosus; and/or

In particular wherein the enzyme is used in immobilized form, in particular immobilized on a support, preferably a polymeric organic support, more preferably having hydrophobic properties, even more preferably immobilized on a support based on poly (meth) acrylic resins; and/or

In particular wherein the enzyme is used in an amount in the range of from 0.001 to 20 wt. -%, in particular in the range of from 0.01 to 15 wt. -%, preferably in the range of from 0.1 to 15 wt. -%, preferably in the range of from 0.5 to 10 wt. -%, based on the total amount of the compound to be hydrolyzed; and/or

In particular, the enzyme is recycled after the reaction.

20. The method of any one of claims 1 and 10 to 19,

wherein, according to scheme (B), the hydrolysis of the acyl group, in particular of the acetyl group, is carried out at a temperature in the range of from 10 ℃ to 80 ℃, in particular in the range of from 20 ℃ to 80 ℃, preferably in the range of from 25 ℃ to 75 ℃, more preferably in the range of from 45 ℃ to 75 ℃, still more preferably in the range of from 50 ℃ to 70 ℃; and/or

Wherein, according to scheme (B), the hydrolysis of the acyl group, in particular of the acetyl group, is carried out at a pressure in the range of 0.0001 to 10 bar, in particular in the range of 0.001 to 5 bar, preferably in the range of 0.01 to 2 bar, more preferably in the range of 0.05 to 1 bar, even more preferably about 1 bar;

wherein, according to scheme (B), the hydrolysis of acyl groups, in particular acetyl groups, is carried out in the presence of water.

21. The method of any one of claims 1 and 10 to 20,

wherein, according to scheme (B), the compounds of general formula (Ib) as defined above can be obtained and/or obtained by reacting a carboxylic anhydride of general formula (V) with 3-hydroxybutyric acid,

R²-O-R²(V)

wherein the radical R²Having the above definitionsAs defined above, acetic anhydride or propionic anhydride is particularly preferred, acetic anhydride being preferred.

22. The method of claim 21, wherein the first and second light sources are selected from the group consisting of,

wherein the reaction of the carboxylic anhydride of the general formula (V) with 3-hydroxybutyric acid is carried out according to the following reaction scheme,

wherein the radical R²Have the meaning defined above.

23. The method according to claim 21 or 22,

wherein the reaction of acetic anhydride with 3-hydroxybutyric acid is carried out according to the following reaction scheme

Wherein the group Ac represents an acetyl group.

24. The method of any one of claims 21 to 23,

wherein the reaction of the carboxylic anhydride of the general formula (V) as defined above with 3-hydroxybutyric acid is carried out at a temperature in the range from 60 to 150 ℃, in particular in the range from 70 to 120 ℃, preferably in the range from 80 to 100 ℃; and/or

Wherein the reaction of the carboxylic anhydride of the general formula (V) with 3-hydroxybutyric acid as defined above is carried out at a pressure in the range of from 0.0001 bar to 10 bar, in particular in the range of from 0.001 bar to 5 bar, preferably in the range of from 0.01 bar to 2 bar, more preferably in the range of from 0.05 bar to 1 bar, even more preferably at about 1 bar.

25. The method of any one of claims 1 and 10 to 24,

wherein, according to the synthetic route (B),

(a) in a first process step (a), a carboxylic anhydride of the formula (V) as defined previously is reacted with 3-hydroxybutyric acid to give a compound of the formula (Ib) as defined above,

R²-O-R²(V)

wherein R is²Having the meaning defined above, in particular acetic anhydride or propionic anhydride, preferably acetic anhydride; followed by

(b) In a second process step (b), the thus obtained compound of the general formula (Ib) as defined above is reacted with a compound selected from C as defined above₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) reaction of fatty alcohols; followed by

(c) In a third process step (c), the acyl group is hydrolyzed,

thus, as the reaction product (III), C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

26. The method of any one of claims 1 and 10 to 25,

wherein, according to scheme (B), C of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is obtained as reaction intermediate (IIIa) prior to hydrolysis of acyl, in particular acetyl₁₀-C₃₀Esters of fatty alcohols, in particular acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated fatty C esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₃₀Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated aliphatic C esters acylated with 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄-a fatty alcohol ester; and/or

Wherein, according to scheme (B), the derivative derived from C is obtained as reaction intermediate (IIIa) before the hydrolysis of the acyl group, in particular acetyl group₁₀-C₃₀Carboxylic esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched C₁₀-C₂₄Carboxylic esters of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₃₀-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols.

In particular wherein C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-fatty alcohols selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (elaidyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

27. The method of any one of claims 1 and 10 to 26,

wherein, according to scheme (B), a primary C of monobasic origin derived from a linear, saturated or mono-or polyunsaturated aliphatic group is obtained as reaction intermediate (IIIa) before hydrolysis of the acyl group, in particular the acetyl group₁₀-C₂₄Acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols.

28. The method of any one of claims 1 and 10 to 27,

wherein, according to scheme (B), the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of general formula (IIIa) is obtained as reaction intermediate (IIIa) before the hydrolysis of the acyl group, in particular the acetyl group

CH₃-CH(OR²)-CH₂-C(O)OR³(IIIa)，

Wherein, in the general formula (IIIa),

·R²represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group) and (C) in the presence of a water-soluble polymer,

·R³denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀Alkyl, preferably C₁₀-C₂₄-an alkyl group;

in particular wherein the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, Cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

29. The method according to any one of the preceding claims,

wherein the fatty alcohol (II) corresponds to the general formula (II')

R³-OH(II’)，

Wherein the radical R³Denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-alkyl groups, in particular wherein the hydroxyl function (OH function) is primary and/or terminal.

30. The method of claim 29, wherein the first and second portions are selected from the group consisting of,

wherein the radical R³Representing linearitySaturated or mono-or polyunsaturated aliphatic C₁₀-C₂₄-alkyl groups, in particular wherein the hydroxyl function (OH function) is primary and/or terminal; and/or

Wherein the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, Cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

31. The method according to any one of the preceding claims,

wherein the fatty alcohol (II) is selected from linear or branched, saturated or mono-or polyunsaturated fatty C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄Fatty alcohols, preferably having primary and/or terminal hydroxyl functions (OH functions); and/or

Wherein the fatty alcohol (II) is selected from linear, saturated or mono-or polyunsaturated, aliphatic mono-and preferably primary C₁₀-C₃₀Fatty alcohols, in particular linear, saturated or monounsaturated or polyunsaturated, aliphatic monohydric and preferably primary C₁₀-C₂₄A fatty alcohol; and/or

Wherein the fatty alcohol (II) is selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans-oleyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

32. The method according to any one of the preceding claims,

wherein, as the reaction product (III), C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄Linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of fatty alcohols, preferably of 3-hydroxybutyric acid₁₀-C₃₀Linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of fatty alcohols, preferably of 3-hydroxybutyric acid₁₀-C₂₄A fatty alcohol ester.

33. The method according to any one of the preceding claims,

wherein, as reaction product (III), a compound derived from C is obtained₁₀-C₃₀Carboxylic esters of 3-hydroxybutyric acid of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C₁₀-C₃₀-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated, aliphatic mono-and preferably primary C₁₀-C₂₄-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols.

34. The method according to claim 32 or 33,

wherein, C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-the fatty alcohol is selected from the group of: 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre lipid alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol),Cis-9-hexadecen-1-ol (palmitoleic alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans oleyl alcohol), cis-11-octadecen-1-ol, cis-9, 12-octadecadien-1-ol (linoleyl alcohol), 6,9, 12-octadecatrien-1-ol (gamma-linolenyl alcohol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

35. The method according to any one of the preceding claims,

wherein, as reaction product (III), a 3-hydroxybutyric acid fatty alcohol ester CH of the general formula (III') is obtained₃-CH(OH)-CH₂-C(O)OR³ (III’)，

Wherein the radical R³Denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-an alkyl group.

36. The method of claim 35, wherein the first and second components are selected from the group consisting of,

wherein, in the general formula (III'), the group R³Denotes linear, saturated or monounsaturated or polyunsaturated C₁₀-C₂₄An aliphatic alkyl group.

37. The method of claim 35 or 36,

wherein, in the general formula (III'), the group R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, Cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

38. The method according to any one of the preceding claims,

wherein the unreacted starting compounds (Ia) or (Ib) and/or (II) are separated from the reaction product (III) and/or (in the case of scheme (B)) from the reaction intermediate (IIIa) and subsequently recycled.

39. A reaction product, in particular a (chemical) product, in particular a reaction product (III), preferably a fatty alcohol ester of 3-hydroxybutyric acid, obtainable by a process according to any one of the preceding claims.

40. The reaction product according to claim 39, obtainable by scheme (A) and/or scheme (B).

41. A fatty alcohol ester of 3-hydroxybutyric acid, in particular the reaction product according to claim 39 or 40,

wherein the fatty alcohol ester of 3-hydroxybutyric acid is C of 3-hydroxybutyric acid₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄Linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of fatty alcohols, preferably of 3-hydroxybutyric acid₁₀-C₃₀Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated fatty C esters of 3-hydroxybutyric acid₁₀-C₂₄A fatty alcohol ester.

42. A fatty alcohol ester of 3-hydroxybutyric acid, in particular the reaction product according to claim 39 or 40, in particular the fatty alcohol ester of 3-hydroxybutyric acid according to claim 41,

wherein the fatty alcohol ester of 3-hydroxybutyric acid is derived from C₁₀-C₃₀Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, in particular derived from C₁₀-C₂₄Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C₁₀-C₃₀Carboxylic acid esters of 3-hydroxybutyric acid of aliphatic alcohols, preferably derived from linear or branched, saturated or unsaturated alcoholsMono-or polyunsaturated, aliphatic, mono-and preferably primary C₁₀-C₂₄Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols.

43. The fatty alcohol ester of 3-hydroxybutyric acid of claim 41 or 42,

wherein, C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-the fatty alcohol is selected from the group of: 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre lipid alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-behenyl alcohol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (elaidyl alcohol), cis-11-octadecen-1-ol, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (gamma-linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

44. A fatty alcohol ester of 3-hydroxybutyric acid, in particular the reaction product according to claim 39 or 40, in particular the fatty alcohol ester of 3-hydroxybutyric acid according to any one of claims 41 to 43,

wherein the fatty alcohol ester of 3-hydroxybutyric acid corresponds to formula (III')

CH₃-CH(OH)-CH₂-C(O)OR³(III’)

Wherein the radical R³Denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-an alkyl group.

45. The fatty alcohol ester of 3-hydroxybutyric acid of claim 44,

wherein, in the general formula (III'), the group R³Denotes linear, saturated or monounsaturated or polyunsaturated aliphatic C₁₀-C₂₄-an alkyl group.

46. The fatty alcohol ester of 3-hydroxybutyric acid of claim 44 or 45,

wherein, in the general formula (III'), the group R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, Cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

47. A reaction intermediate, in particular a (chemical) product, in particular a reaction intermediate (IIIa), preferably a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid), obtainable according to the process of any one of the preceding process claims, according to scheme (B) before the hydrolysis of the acyl group.

48. A fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid), in particular a reaction intermediate according to claim 47,

wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is C of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₃₀Esters of fatty alcohols, in particular acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated C acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₃₀Aliphatic fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated C acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄-an aliphatic fatty alcohol ester.

49. A fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid), particularly a reaction intermediate according to claim 47, particularly a fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to claim 48,

wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is derived from C₁₀-C₃₀Carboxylic esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated, aliphatic mono-and preferably primary C₁₀-C₃₀-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated, aliphatic mono-and preferably primary C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols;

wherein the acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is acetylated 3-hydroxybutyrate (3-acetoxybutyrate).

50. The fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid) of claim 48 or 49,

wherein, C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-fatty alcohols selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (elaidyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol); and/or

Wherein the acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is acetylated 3-hydroxybutyrate (3-acetoxybutyrate).

51. A fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid), particularly a reaction intermediate according to claim 47, particularly a fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to any one of claims 48 to 50,

wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is derived from a linear, saturated or mono-or polyunsaturated aliphatic, primary C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols.

52. A fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid), particularly a reaction intermediate according to claim 47, particularly a fatty alcohol ester of an acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to any one of claims 48 to 51,

wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is a fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of the general formula (IIIa)

CH₃-CH(OR²)-CH₂-C(O)OR³ (IIIa)，

Wherein, in the general formula (IIIa),

·R²represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group) and (C) in the presence of a water-soluble polymer,

·R³denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀Alkyl, preferably C₁₀-C₂₄-an alkyl group;

in particular wherein the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group)) 1-hexacosanyl (waxy base), 1-octacosyl (montanyl), 1-triacontyl (melissic base), cis-9-hexadecen-1-yl (palmityl base), cis-9-octadecen-1-yl (oleyl base), trans-9-octadecen-1-yl (trans oleyl base), cis-11-octadecen-1-yl, cis-9, 12-octadecadien-1-yl (linoleyl base) or 6,9, 12-octadecatrien-1-yl (gamma-linolenyl), preferably cis-9-octadecen-1-yl (oleyl base).

53. A pharmaceutical composition, in particular a medicament (drug product) or pharmaceutical agent, comprising the reaction product according to claim 39 or 40, and/or the fatty alcohol ester of 3-hydroxybutyrate according to any one of claims 41 to 46, or the reaction intermediate according to claim 47, and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to any one of claims 48 to 52.

54. Pharmaceutical composition according to claim 53 for the prophylactic and/or therapeutic treatment, or for the prophylactic and/or therapeutic treatment of a disease of the human or animal body, in particular a disease associated with a disturbance of energy metabolism, in particular ketone body metabolism, such as in particular craniocerebral trauma, stroke, hypoxia, a cardiovascular disease such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, a neurodegenerative disease such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, a fat metabolism disease such as glucose transport deficiency (GLUT1 deficiency), VL-FAOD and a mitochondrial disease such as mitochondrial thiolase deficiency, Huntington's disease, a cancer such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, a rheumatic disease, such as rheumatoid arthritis and uricosuric arthritis, a gastrointestinal disease, such as chronic inflammatory bowel disease, particularly ulcerative colitis and crohn's disease, lysosomal storage diseases, such as sphingolipid disorders, particularly niemann-pick disease, diabetes and the effects or side effects of chemotherapy.

55. The reaction product according to claim 39 or 40, and/or the fatty alcohol ester of 3-hydroxybutyrate according to any one of claims 41 to 46, or the reaction intermediate according to claim 47, and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to any one of claims 48 to 52 for use in the prophylactic and/or therapeutic treatment or for use in the prophylactic and/or therapeutic treatment of human or animal body disorders, particularly disorders associated with disturbances of energy metabolism, particularly ketone body metabolism, such as in particular craniocerebral trauma, stroke, hypoxia, cardiovascular disorders such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative disorders such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis, lipid 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 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 sphingolipid diseases, in particular niemann-pick disease, the effects or side effects of diabetes and chemotherapy.

56. Use of the reaction product of claim 39 or 40, and/or the fatty alcohol ester of 3-hydroxybutyrate of any one of claims 41 to 46, or the reaction intermediate of claim 47, and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyrate) of any one of claims 48 to 52, for the prophylactic and/or therapeutic treatment or for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of a disease of the human or animal body, particularly a disease associated with a disturbance of energy metabolism, particularly ketone body metabolism, such as particularly craniocerebral trauma, stroke, hypoxia, a cardiovascular disease such as myocardial infarction, refeeding syndrome, anorexia, epilepsy, a neurodegenerative disease such as dementia, Alzheimer's disease, Parkinson's disease, Multiple sclerosis and amyotrophic lateral sclerosis, disorders of fat metabolism 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 lymphoma, astrocytoma and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and uric acid arthritis, gastrointestinal disorders such as chronic inflammatory bowel disease, in particular ulcerative colitis and crohn's disease, lysosomal storage diseases such as sphingolipid disorders, in particular niemann-pick disease, the effects or side effects of diabetes and chemotherapy.

57. Use of the reaction product of claim 39 or 40, and/or the fatty alcohol ester of 3-hydroxybutyrate of any one of claims 41 to 46, or the reaction intermediate of claim 47, and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) of any one of claims 48 to 52, in, or in the manufacture of a medicament for, prophylactic and/or therapeutic treatment, or for a catabolic state, such as starvation, dietetic or low carbohydrate nutrition.

58. A foodstuff and/or foodstuff comprising the reaction product of claim 39 or 40, and/or the fatty alcohol ester of 3-hydroxybutyrate of any one of claims 41 to 46, or the reaction intermediate of claim 47, and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) of any one of claims 48 to 52.

59. The food and/or foodstuff of claim 58, wherein the food and/or foodstuff is a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy treat, an appetite suppressant or a strength and/or endurance exercise supplement.

60. Use of the reaction product of claim 39 or 40, and/or the fatty alcohol 3-hydroxybutyrate of any one of claims 41 to 46, or the reaction intermediate of claim 47, and/or the acylated fatty alcohol 3-hydroxybutyrate (3-acyloxybutyrate) of any one of claims 48 to 52 in food and/or foodstuff.

61. The use according to claim 60, wherein the food and/or foodstuff is a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy treat, an appetite suppressant or a strength and/or endurance exercise supplement.

Technical Field

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

In particular, the present invention relates to a process for the production of fatty alcohol esters of 3-hydroxybutyric acid, as well as to the reaction products obtained thereby or prepared thereby (i.e. fatty alcohol esters of 3-hydroxybutyric acid) and to their use, in particular in pharmaceutical compositions (e.g. pharmaceuticals (medicines) or medicaments) or in food and/or foodstuff, and to their further applications or uses.

The present invention also relates to a process for the production of acylated (e.g. acetylated) fatty alcohol esters of 3-hydroxybutyrate (i.e. in other words fatty alcohol esters of 3-acyloxybutyric acid (e.g. 3-acetoxybutyric acid)), the reaction products thus obtained or prepared (i.e. fatty alcohol esters of acylated 3-hydroxybutyrate, i.e. fatty alcohol esters of 3-acyloxybutyric acid (e.g. 3-acetylbutyric acid)) and their use, in particular in pharmaceutical compositions (e.g. pharmaceuticals (medicines) or medicaments) or in food and/or foodstuff, and their further applications or uses.

Furthermore, the present invention relates to a pharmaceutical composition, in particular a medicament (drug product) or pharmaceutical agent, comprising the reaction product (i.e. the fatty alcohol ester of 3-hydroxybutyric acid and acylated derivatives thereof) obtainable or produced according to the process of the present invention, and uses or applications thereof.

Finally, the present invention relates to a food and/or foodstuff, in particular a food supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy snack, an appetite suppressant and a strength and/or endurance sport supplement, comprising a reaction product (i.e. a fatty alcohol ester of 3-hydroxybutyric acid and acylated derivatives thereof) obtainable or produced according to the process of the present invention, and uses or uses thereof.

Background

In human energy metabolism, glucose is a short-term available energy carrier, metabolized into energy in mitochondria by the release of water and carbon dioxide. Glycogen stores of the liver have been emptied during night sleep. However, the Central Nervous System (CNS) and the heart, in particular in humans, require a permanent energy supply.

Physiological substitutes for glucose, which are mainly used in the central nervous system, are the so-called ketone bodies.

The term ketone bodies is especially a collective term for three compounds which are formed primarily in catabolic states (e.g., starvation, reduced diet or low carbohydrate diet) and may lead to ketosis. The term ketone body specifically includes three compounds: acetoacetate (also referred to synonymously as acetoacetate) and acetone and also 3-hydroxybutyrate (also referred to synonymously hereinafter as beta-hydroxybutyrate or BHB or 3-BHB) or its salts (i.e. 3-hydroxybutyrate or beta-hydroxybutyrate), the latter being the most important of the three compounds mentioned above. 3-hydroxybutyric acid or its salts occur physiologically as the (R) -enantiomer, i.e. as (R) -3-hydroxybutyric acid (synonymously also referred to as (3R) -3-hydroxybutyric acid, to emphasize the chiral center in the 3-position) or its salts.

These ketone bodies are also physiologically supplied in large quantities by lipolysis of lipids stored in the body when fasted or starved and almost completely replace the energy source glucose.

Ketone bodies formed in the liver are derived from acetyl-CoA (═ acetyl CoA), which is derived from beta oxidation; they are a transportable form of acetyl-coa in humans. However, in order to utilize ketone bodies, the brain and muscles must first adapt by expressing the enzymes required to convert ketone bodies back to acetyl-coa. Especially during starvation, ketone bodies contribute significantly to energy production. For example, after a period of time, the brain can only become overactive with one third of the daily glucose amount.

Physiologically, ketone bodies are synthesized from two molecules of activated acetic acid in the form of acetyl-CoA, a normal intermediate in fatty acid degradation, which is extended to intermediate 3-hydroxy-3 methyl-glutaryl-CoA (HMG-CoA) using a further acetyl-CoA unit and the enzyme HMG-CoA-synthetase, where finally HMG-CoA-lyase cleaves acetoacetate. These three steps occur only in the mitochondria of the liver (the rennin 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.

Spontaneous decarboxylation converts acetoacetate to acetone; it is occasionally perceived in the breath of diabetics and dieters. It cannot be used further by the body. However, the proportion of acetone in the ketone bodies is small.

Thus, acetoacetate is reductively converted to the physiologically relevant form of 3-hydroxybutyrate or 3-hydroxybutyrate, but can also decompose to acetone which is physiologically unusable and liberate carbon dioxide which is detectable and olfactory detectable in the urine and exhaled air of patients with severe ketosis, ketoacidosis (e.g., type 1 diabetes patients without insulin replacement).

3-hydroxybutyric acid is currently used and sold in the weight training field as sodium, magnesium or calcium salt.

However, from an evolutionary point of view, humans are not aware of 3-hydroxybutyrate, or are aware of very small amounts, since plants do not produce 3-hydroxybutyrate, whereas 3-hydroxybutyrate in animals is only present in lean animals which die from ketosis, and thus 3-hydroxybutyrate when administered orally can cause nausea. The free acid form of 3-hydroxybutyric acid and its salts also tastes bitter, causing severe vomiting and nausea.

Furthermore, patients (especially newborns, also including adults) cannot tolerate large amounts of salts of 3-hydroxybutyrate for long periods of time because these compounds can have kidney-damaging effects.

Furthermore, 3-hydroxybutyrate and its salts have a very short plasma half-life, and ketosis lasts only about three to four hours even with a few grams of medication, i.e., patients do not continue to benefit from treatment with 3-hydroxybutyrate or its salts, especially at night. In the case of metabolic diseases, this may lead to life-threatening situations.

Thus, in the context of treating such metabolic diseases, so-called medium chain triglycerides, so-called MCTs, are currently used for ketogenic therapy, i.e. caproic, caprylic and capric acids (i.e. saturated linear C) expected from the corresponding triglycerides₆-、C₈-and C₁₀-fatty acids).

Basically, however, from a pharmaceutical and clinical point of view, 3-hydroxybutyric acid is a more potent pharmaco-pharmacological target molecule that, according to the prior art, can be used in principle for the treatment of various diseases, but cannot be used due to lack of physiological compatibility (e.g. diseases associated with disorders of energy metabolism, in particular of ketone body metabolism, or neurodegenerative diseases such as dementia, alzheimer's disease, parkinson's disease, etc., disorders of fat metabolism, etc.).

The following table illustrates only the surname (in no way limiting) potential treatment options or possible indications for the active ingredient 3-hydroxybutyrate.

Therefore, from a pharmaceutical and clinical point of view, it would be desirable to be able to find effective precursors or metabolites that physiologically allow to obtain 3-hydroxybutyrate or its salts directly or indirectly, in particular in the physiological metabolism of the human or animal body.

Thus, the prior art is not devoid of any attempt to find physiologically suitable precursors or metabolites of 3-hydroxybutyric acid or its salts. However, no effective compound has been found in the prior art to date. Furthermore, according to the prior art, it is not possible or not easily possible to obtain such compounds.

Disclosure of Invention

The problem underlying the present invention is therefore to provide an efficient process for the production of physiologically suitable or physiologically compatible precursors and/or metabolites of 3-hydroxybutyrate (i.e. β -hydroxybutyrate or BHB or 3-BHB) or salts thereof.

Such a method should in particular allow the corresponding BHB precursors and/or BHB metabolites to be obtained in an efficient manner, in particular in large amounts and without large amounts of toxic by-products.

In a completely surprising manner, the applicant has now found 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 an effective and physiologically effective or physiologically compatible precursor and/or metabolite of the ketone body 3-hydroxybutyric acid or of a salt thereof, and has been able to find or develop effective processes for the production of these compounds which allow direct and effective, in particular economical and industrially feasible, access to these compounds.

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 a fatty alcohol ester of 3-hydroxybutyric acid (β -hydroxybutyric acid, BHB or 3-BHB) according to claim 1; furthermore, particular special and/or advantageous embodiments of the inventive method are the subject matter of the relevant dependent claims.

Furthermore, according to a second aspect of the present invention, the present invention relates to a reaction product obtainable according to the process of the present invention according to the independent claims (claims 39 and 40), or a fatty alcohol ester of 3-hydroxybutyrate (β -hydroxybutyrate, BHB or 3-BHB) according to the respective claims (claims 41 to 46), and a reaction intermediate obtainable according to the process of the present invention according to the independent claims (claim 47), or a fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) according to the respective claims (claims 48 to 52); furthermore, particularly specific and/or advantageous embodiments of this aspect of the invention are the subject matter of the relevant dependent claims.

Likewise, according to a third aspect of the present invention, the present invention relates to a pharmaceutical composition, in particular a medicament (drug) or medicament, according to the respective independent claim (claim 53); furthermore, particularly specific and/or advantageous embodiments of this aspect of the invention are the subject matter of the relevant dependent claims.

Furthermore, according to a fourth aspect of the present invention, the present invention relates to the reaction product according to the invention of 3-hydroxybutyrate (β -hydroxybutyrate, BHB or 3-BHB) or the fatty alcohol ester according to the present invention and the reaction intermediate according to the present invention of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) or the fatty alcohol ester according to the present invention, as claimed in the respective independent claims (claim 55), in each case for the prophylactic and/or therapeutic treatment, or in each case for the prophylactic and/or therapeutic treatment of a disease of the human or animal body.

Furthermore, according to a fifth aspect of the present invention, the present invention relates to the use of the reaction product according to the invention of 3-hydroxybutyrate (β -hydroxybutyrate, BHB or 3-BHB) or the fatty alcohol ester according to the present invention and the reaction intermediate according to the invention of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) or the fatty alcohol ester according to the present invention, in each case for the prophylactic and/or therapeutic treatment, or in each case for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of a disease of the human or animal body.

Furthermore, according to a sixth aspect of the present invention, the present invention relates to the use of the inventive reaction product of 3-hydroxybutyrate (β -hydroxybutyrate, BHB or 3-BHB) or the inventive fatty alcohol ester according to the associated independent claim (claim 57), and the inventive reaction intermediate of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) or the inventive fatty alcohol ester, in each case for prophylactic and/or therapeutic treatment, or in each case for the manufacture of a medicament for prophylactic and/or therapeutic treatment, or for the catabolic state.

Furthermore, according to a seventh aspect of the invention, the invention relates to a food and/or foodstuff product according to the related independent claim (claim 58); furthermore, particularly specific and/or advantageous embodiments of the food and/or foodstuff according to the invention are the subject matter of the relevant dependent claims.

Finally, according to an eighth aspect of the present invention, the present invention relates to the use of the inventive reaction product of 3-hydroxybutyrate (β -hydroxybutyrate, BHB or 3-BHB) or the inventive fatty alcohol ester and the inventive reaction intermediate of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) or the inventive fatty alcohol ester in foods and/or foodstuffs according to the related independent claim (claim 60); furthermore, particularly special and/or advantageous embodiments of the use according to the invention are the subject matter of the use-related dependent claims.

It goes without saying that, in order to avoid repetitions, the following features, embodiments, advantages, etc., which are listed below only for one aspect of the invention, naturally also apply correspondingly for the other aspects of the invention, without this needing to be mentioned separately.

Furthermore, it goes without saying that the various aspects and embodiments of the invention are also considered to be disclosed in any combination with other aspects and embodiments of the invention, in particular any combination of features and embodiments, since it originates from the back reference of all patent claims and is also considered to be widely disclosed with respect to all resulting combination possibilities.

With regard to all the relative or percentage data on a weight basis, in particular relative amounts or weight data, provided below, 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 the components or ingredients defined below; however, this is self-evident to the skilled person.

Furthermore, if desired, the skilled person can deviate from the following range specifications without departing from the scope of the invention.

Furthermore, all values or parameters or the like specified below apply in principle to the determination or identification which can be carried out by standardized or explicitly specified determination methods or other determination or measurement methods familiar to the person skilled in the art.

Having said this, the invention will be described in more detail below:

according to a first aspect of the invention, the subject of the invention is thus a process for the production of fatty alcohol esters of 3-hydroxybutyric acid (beta-hydroxybutyric acid, BHB or 3-BHB),

(A) wherein, according to (first) scheme (A), at least one compound of formula (Ia) is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols,

CH₃-CH(OH)-CH₂-C(O)R¹ (Ia)

wherein, in the general formula (Ia), the group R¹Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl;

or

(B) Wherein, according to (second, alternative to (A) of scheme (B), at least one compound of general formula (Ib) is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols, followed by hydrolysis of the acyl group,

CH₃-CH(OR²)-CH₂-C(O)-O-C(O)-CH₂-CH(OR²)-CH₃ (Ib)

wherein, in the general formula (Ib), the group R²Represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group);

thus, as reaction product (III), in each case C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

As mentioned above, the applicant has very surprisingly found that the fatty alcohol esters of 3-hydroxybutyric acid (β -hydroxybutyric acid, BHB or 3-BHB) (synonymously also referred to as "fatty alcohol esters of 3-hydroxybutyric acid", among others) and the reaction intermediates (i.e. fatty alcohol esters of acylated 3-hydroxybutyric acid or fatty alcohol esters of 3-acyloxybutyric acid) prior to the acyl hydrolysis according to the synthetic route (B) are each effective, since the physiologically compatible precursors and/or metabolites of 3-hydroxybutyric acid or its salts can also be used in large amounts in medical or clinical applications, since they are physiologically compatible.

The above-mentioned fatty alcohol ester of 3-hydroxybutyric acid or acylated fatty alcohol ester of 3-hydroxybutyric acid, which may be efficiently obtained for the first time by the production method according to the present invention, represents a physiologically and pharmacologically relevant substitute for free 3-hydroxybutyric acid or its salt.

The production of 3-hydroxybutyric acid or acylated fatty alcohol esters of 3-hydroxybutyric acid by conventional organic synthesis is complicated and costly, 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 operating production process is provided, by means of which 3-hydroxybutyric acid or fatty alcohol esters of acylated 3-hydroxybutyric acid can be produced, in particular, in one step, without undesirable side reactions.

The process of the invention therefore makes it possible for the first time to provide nontoxic 3-hydroxybutyric acid or fatty alcohol esters of acylated 3-hydroxybutyric acid from known, commercially available and in particular physiologically harmless components or educts (starting compounds). The thus produced fatty alcohol ester of 3-hydroxybutyric acid or acylated 3-hydroxybutyric acid may be physiologically decomposed, particularly in the stomach and/or intestine, and release or produce the target molecule "3-hydroxybutyric acid" or a salt thereof as an active ingredient or active component.

Furthermore, the above-mentioned fatty alcohol ester of 3-hydroxybutyric acid or acylated 3-hydroxybutyric acid also contains an acceptable taste to ensure compatibility even when orally administered in a large amount over a long period of time (e.g., at a daily administration dose of 50g or more). .

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

Furthermore, the process can also be carried out enantioselectively with suitable starting materials. For example, according to the invention, the production method allows the biologically relevant form (i.e. (R) -enantiomer) to be enriched, in particular catalyzed by enzymes, so that it does not burden the renal system of the patient (i.e. it is removed by the kidneys) when administered orally. However, in principle, enrichment of the (S) -enantiomer is also possible and may be useful under certain conditions.

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

In particular, the production process of the invention uses commercially available or readily available starting compounds and furthermore allows relatively simple process management even in the case of large-scale implementation.

In contrast to conventional prior art production processes, the production process according to the invention does not use complex starting materials, but only a single step. However, excellent yields are achieved according to the present invention, wherein the formation of by-products is minimized or avoided.

Furthermore, the process of the invention is simple and economical. In particular, the process according to the invention is generally 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); thus, the obtained reaction product is not contaminated by solvent and there is no need to remove and dispose of or recycle solvent in an expensive and energy-consuming manner after carrying out the process or reaction. Furthermore, no toxic by-products are formed.

If desired, the crude reaction product obtained according to the production process of the present 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.).

Synthetic route (A)

The following review relates to scheme (A) of the process of the present invention.

According to a particular embodiment of the present invention, the compounds of general formula (Ia) can be used in racemic form or in (R) -enantiomeric form, depending on the synthesis scheme (a). The (R) configuration refers to the chiral carbon atom at position 3 of the compound of formula (Ia).

According to the invention, it is preferred that, according to scheme (A), in formula (I), the group R¹Represents an ethyl group.

In other words, it is preferred according to the invention that, as compounds of the general formula (Ia), according to scheme (A), use is made of the formula CH₃-CH(OH)-CH₂-C(O)OC₂H₅Ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate).

This makes possible particularly efficient process control and high yields with minimized or suppressed formation of by-products. In addition, ethyl 3-hydroxybutyrate is also commercially available in large quantities and can also be converted more efficiently than the free acid (i.e., 3-hydroxybutyrate). In particular, ethyl 3-hydroxybutyrate can be obtained on a large scale as a starting compound, for example by claisen condensation of ethyl acetate.

In particular, in the process of the present invention, the reaction is carried out without solvent and/or without any solvent according to scheme (a). This means that the reaction is carried out as a mass reaction, a mass reaction or a so-called bulk reaction. This has the advantage that the reaction product obtained is not contaminated with solvent and that 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. Surprisingly, the process or reaction is still carried out with high conversion and yield and at least substantially without significant by-product formation.

According to a particular embodiment of the present invention, according to scheme (a), the reaction can be carried out in the presence of a catalyst, in particular an enzyme and/or a metal-and/or metal-based acidic or basic catalyst, preferably in the presence of an enzyme. In this particular embodiment, it is preferred that the catalyst is recycled after the reaction.

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

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 attachment of two or more molecules through a covalent bond. Catalase in the sense of the present invention is in particular an enzyme capable of converting hydrogen peroxide into oxygen and water. The term esterase refers in particular to an enzyme capable of hydrolytic cleavage of an ester into an alcohol and an acid (saponification); these are therefore in particular hydrolases, where lipolytic esterases are also referred to as lipases. In the sense of the present invention, lipases are in particular enzymes which are capable of separating free fatty acids from lipids, such as glycerides (lipolysis).

In the context of the present invention, the enzymes used as catalysts according to the synthesis route (A) may in particular be derived from Candida antarctica, Mucor miehei (Mucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus dysarii and Pseudomonas species, and combinations thereof, preferably from Candida antarctica, Mucor miehei (Mucor miehei) and Thermomyces lanuginosus.

According to a particular embodiment, according to scheme (A), the enzyme can be used in immobilized form, immobilized on a support, preferably on a polymeric organic support, more preferably hydrophobic, even more preferably on a poly (meth) acrylic resin-based support.

As explained above with respect to the general use of catalysts, when an enzyme is used as a catalyst according to scheme (a), it is preferred to recycle the enzyme after the reaction.

According to this particular embodiment of the process of the invention, according to scheme (A), each of the commercially available enzymes defined above may be used as the enzyme described above (for example, CALB lipase on a polymeric support derived from Candida antarctica, for example from Sigma Aldrich or Merck435 or from Strem Chemicals, IncStrem 435)。

If the reaction according to scheme (A) is carried out in the presence of an enzyme as catalyst within the framework of the production process of the invention, it is preferred that the reaction is carried out at a temperature in the range from 10 ℃ to 80 ℃, in particular in the range from 20 ℃ to 80 ℃, preferably in the range from 25 ℃ to 75 ℃, more preferably in the range from 45 ℃ to 75 ℃ and still more preferably in the range from 50 ℃ to 70 ℃.

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

According to one embodiment of the present invention, if the reaction is carried out in the presence of an enzyme as catalyst according to scheme (A), the range of the applied pressure can also vary within wide limits. In particular, if the reaction is carried out in the presence of an enzyme as catalyst, the reaction may be carried out at a pressure in the range of from 0.0001 bar to 10 bar, in particular in the range of from 0.001 bar to 5 bar, preferably in the range of from 0.01 bar to 2 bar, more preferably in the range of from 0.05 bar to 1 bar, even more preferably at about 1 bar.

According to an alternative embodiment of the present invention, the reaction according to scheme (a) can also be carried out in the presence of metal-containing and/or metal-based acidic or basic catalysts.

According to this alternative embodiment of the invention, according to scheme (A), the reaction is carried out in the presence of an acidic or basic catalyst containing a metal and/or metal base, which may be chosen in particular from (i) basic catalysts, in particular alkali or alkaline earth metal hydroxides and alkali or alkaline earth metal alcoholates, such as NaOH, KOH, LiOH, Ca (OH)₂NaOMe, KOMe and sodium tert-butoxide, (ii) acidic catalysts, especially inorganic and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) lewis acids, especially 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, especially based on mineral silicates, germanates, carbonates and aluminas, such as zeolites, montmorillonites, mordenite, hydrotalcite and alumina, and combinations thereof.

According to this embodiment, in particular, alkali or alkaline earth alcoholates can be used as catalysts according to scheme (a).

In particular, also according to this embodiment, it is preferred, according to scheme (a), to recycle the catalyst based on the metal-containing and/or metal-based acidic or basic catalyst after the reaction.

If, according to a particular embodiment of the present invention, the reaction according to scheme (a) is carried out in the presence of a metal-and/or metal-based acidic or basic catalyst, the temperature can vary within wide limits. In particular, the reaction is carried out at a temperature in the range from 20 ℃ to 150 ℃, in particular in the range from 50 ℃ to 140 ℃, preferably in the range from 70 ℃ to 130 ℃, more preferably in the range from 80 ℃ to 125 ℃, still more preferably in the range from 100 ℃ to 120 ℃ in the presence of a metal-and/or metal-based acidic or basic catalyst.

Furthermore, also according to this embodiment, the catalyst (i.e. the metal-and/or metal-based acidic or basic catalyst) can also vary within a wide range of contents, depending on the synthesis scheme (a): for example, the amount of catalyst based on the metal-containing and/or metal-based acidic or basic catalyst is in the range of from 0.01 to 30% by weight, in particular in the range of from 0.05 to 15% by weight, preferably in the range of from 0.1 to 15% by weight, and further preferably in the range of from 0.2 to 10% by weight, based on the total amount of starting compounds (Ia) and (II). However, it may deviate from the above amounts for a particular application or individual case without departing from the scope of the present invention.

According to this embodiment of the invention, if the reaction is carried out in the presence of an acidic or basic catalyst containing a metal and/or a metal base according to scheme (a), the pressure range can vary uniformly over a wide range: in particular, the reaction can be carried out in the presence of a metal-and/or metal-based acidic or basic catalyst at a pressure in the range from 0.0001 bar to 10 bar, in particular in the range from 0.001 bar to 5 bar, preferably in the range from 0.01 bar to 2 bar, more preferably in the range from 0.05 bar to 1 bar, more preferably about 1 bar.

This can also vary within wide limits with respect to the amount of starting materials or starting compounds, depending on the synthesis scheme (A).

In view of process economics and optimization of the process procedure, in particular with respect to minimization of by-products, it is advantageous, according to synthesis scheme (a), if the compound of the general formula (Ia) is used in a molar amount in the range of from equimolar to a molar excess of 200 mol-%, in particular in the range of from equimolar to a molar excess of 150 mol-%, preferably in the range of from equimolar to a molar excess of 100 mol-%, based on the hydroxyl groups of the fatty alcohol (II).

Also, in view of process economics and optimization of the process, in particular with respect to minimizing by-products, according to synthesis scheme (a), it is advantageous that the compound of formula (Ia) and the fatty alcohol (II) are used in a molar ratio of compound of formula (I) to 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.

According to a preferred embodiment of the process of the present invention, according to scheme (A), preferably according to scheme (A), at least one compound of formula (Ia') is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) reaction of fatty alcohols;

CH₃-CH(OH)-CH₂-C(O)OC₂H₅ (Ia’)

thus, as the reaction product (III), C of 3-hydroxybutyric acid is obtained₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

Within the scope of the process according to the invention, according to scheme (A), during the reaction, a compound according to general formula (IVa) is simultaneously formed,

R¹-OH (IVa)

wherein, in the general formula (IVa), the group R¹Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl. In particular, it is preferred in this case that the compound according to formula (IVa) is extracted from the reaction according to scheme (a), in particular continuously extracted, in particular preferably continuously removed by distillation.

Synthetic route (B)

The following review relates to scheme (B) of the process of the present invention.

According to a particular embodiment of the present invention, the compounds of general formula (Ib) can be used in racemic form or in (R) -enantiomeric form, depending on the synthesis scheme (B). The (R) -configuration refers to the two chiral carbon atoms of the compound of formula (Ib), i.e. the carbon atoms marked "×" in the following compounds of formula (Ib), each of these chiral centers corresponding to the respective C atom in position 3 of 3-hydroxybutyric acid:

CH₃-C*H(OR²)-CH₂-C(O)-O-C(O)-CH₂-C*H(OR²)-CH₃ (Ib)。

in particular, it is preferred according to the process of the invention that in formula (Ib) according to scheme (B) the radical R²Represents a group-C (O) -CH₃(acetyl) and/or according to scheme (B) as compounds of general formula (Ib) use is made of formula CH₃-CH(OAc)-CH₂-C(O)-O-C(O)-CH₂-CH(OAc)-CH₃Wherein the group Ac represents an acetyl group.

In particular, in the process of the present invention, the reaction is carried out without solvent and/or without any solvent according to scheme (B). This means that the reaction is carried out as a mass reaction or as a so-called bulk reaction. This has the advantage that the reaction product obtained is not contaminated with solvent and that 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. Surprisingly, the process or reaction is still carried out with high conversion and yield and at least substantially without significant by-product formation.

According to a particular embodiment of the process of the invention, the reaction can be carried out in particular autocatalytic or in the presence of a catalyst, in particular a mineral acid, according to scheme (B). Preferably, however, the reaction is carried out in an autocatalytic manner according to scheme (B).

If the reaction according to scheme (B) is carried out in the presence of a catalyst, it is preferred that the reaction according to scheme (B) is carried out in the presence of a mineral acid. In particular, according to this embodiment, the catalyst and/or the mineral acid may be selected from sulfuric acid, hydrohalic acid, phosphoric acid and combinations thereof, according to scheme (B).

Within the scope of the production process of the invention according to scheme (B), it is preferred that the reaction is carried out at a temperature in the range of from 20 ℃ to 150 ℃, in particular in the range of from 50 ℃ to 140 ℃, preferably in the range of from 60 ℃ to 130 ℃, more preferably in the range of from 70 ℃ to 125 ℃, still more preferably in the range of from 75 ℃ to 110 ℃ according to scheme (B).

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

This can also vary within wide limits with respect to the amount of starting materials or starting compounds, depending on the synthesis route (B).

In view of process economics and optimization of the process procedure, in particular with respect to minimization of by-products, it is advantageous if, according to synthesis scheme (B), the compound of the general formula (Ib) is used in a molar amount in the range of from equimolar to a molar excess of 200 mol-%, in particular in the range of from equimolar to a molar excess of 150 mol-%, preferably in the range of from equimolar to a molar excess of 100 mol-%, based on the hydroxyl groups of the fatty alcohol (II).

Also, in view of process economics and optimization of the process procedure, in particular with respect to minimizing by-products, it is advantageous, according to synthesis scheme (B), to use the compound of the general formula (Ib) and the fatty alcohol (II) in a molar ratio of compound of the general formula (Ib)/fatty alcohol (II) in the range of from 1:1 to 10:1, in particular in the range of from 2:1 to 8:1, preferably in the range of from 3:1 to 6: 1.

According to a preferred embodiment of the process according to the invention according to scheme (B), preferably according to scheme (B), at least one compound of formula (Ib') is reacted with a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) of fatty alcohols is reacted followed by hydrolysis of the acyl group;

CH₃-CH(OAc)-CH₂-C(O)-O-C(O)-CH₂-CH(OAc)-CH₃ (Ib’)

wherein, in the general formula (Ib'), the group Ac represents an acetyl group,

thus obtaining C of 3-hydroxybutyric acid as reaction product (III)₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

Within the scope of the process according to the invention, according to scheme (B), during the course of the reaction, a compound according to formula (IVb) is formed simultaneously,

CH₃-CH(OR²)-CH₂-C(O)-OH (IVb)

wherein, in the general formula (IVb), the group R²Represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group). In particular, it is preferred in this case that, according to scheme (B), after the reaction has taken place, the compound according to formula (IVb) is extracted, in particular removed by distillation.

Within the scope of the process of the present invention, the reaction of at least one compound of general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above is followed, according to scheme (B), by hydrolysis of the acyl group formed during this reaction; this reaction therefore also results in the acylation, in particular acetylation or propionylation, of the hydroxy function located in the 3-position of 3-hydroxybutyric acid (i.e.the replacement of the hydrogen atom of the hydroxy function located in the 3-position of 3-hydroxybutyric acid by an acyl group, in particular by acetyl-C (O) -CH)₃Or propionyl-C (O) -C₂H₅Substitution). The hydrolysis of the acyl group carried out according to scheme (B) finally gives the acyl-free reaction product (III). To this end, according to the invention, at least one compound of general formula (Ib) as defined above is reacted, according to scheme (B), with at least one fatty alcohol (II) as defined above, followed by selective or partial hydrolysis of the acyl groups present in the reaction product after the reaction has taken place (═ reaction intermediate). Thus, a reaction product (III) may be obtained, which is defined in that the acyl group is substituted by a hydrogen atom during hydrolysis and thus comprises a free hydroxyl function (i.e. at the position of the reaction product (III), which is back to the 3-position of the 3-hydroxybutyric acid moiety in the reaction product (III)).

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

In particular, according to scheme (B), it is preferred that the enzyme for hydrolyzing acyl groups, in particular acetyl groups, may be selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof. According to the invention, synthetases (synonyms ligase) are in particular enzymes from the ligase class; ligases are enzymes that catalyze the attachment of two or more molecules through a covalent bond. Catalase in the sense of the present invention is in particular an enzyme capable of converting hydrogen peroxide into oxygen and water. The term esterase refers in particular to an enzyme capable of hydrolyzing esters into alcohols and acids (saponification); these are therefore in particular hydrolases, where lipolytic esterases are also referred to as lipases. Lipases in the sense of the present invention are in particular enzymes capable of separating free fatty acids from lipids, such as glycerides (lipolysis).

In particular, according to the scheme (B), the enzymes used for the hydrolysis of acyl groups, in particular acetyl groups, can be derived from Candida antarctica, Mucor miehei (Mucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus dysarii and Pseudomonas species, and combinations thereof, preferably from Candida antarctica, Mucor miehei (Mucor miehei) and Thermomyces lanuginosus.

In particular, according to scheme (B), the enzymes for the hydrolysis of acyl groups, in particular acetyl groups, can be used in immobilized form, in particular on a support, preferably on a polymeric organic support, more preferably having hydrophobic properties, even more preferably on a poly (meth) acrylic resin-based support.

In particular, according to scheme (B), the enzymes used for the hydrolysis of acyl groups, in particular acetyl groups, can be used in an amount in the range from 0.001% to 20% by weight, in particular in the range from 0.01% to 15% by weight, preferably in the range from 0.1% to 15% by weight, preferably in the range from 0.5% to 10% by weight, based on the total amount of the compounds to be hydrolyzed.

According to this embodiment, it is preferred that the enzyme for the hydrolysis of acyl groups, in particular acetyl groups, according to scheme (B), is recycled after the hydrolysis.

According to scheme (B), the hydrolysis of the acyl group, in particular of the acetyl group, can be carried out at a temperature in the range from 10 ℃ to 80 ℃, in particular in the range from 20 ℃ to 80 ℃, preferably in the range from 25 ℃ to 75 ℃, more preferably in the range from 45 ℃ to 75 ℃, still more preferably in the range from 50 ℃ to 70 ℃.

According to scheme (B), the hydrolysis of the acyl group, in particular of the acetyl group, can be carried out at a pressure ranging from 0.0001 bar to 10 bar, in particular from 0.001 bar to 5 bar, preferably from 0.01 bar to 2 bar, more preferably from 0.05 bar to 1 bar, more preferably about 1 bar.

Generally, according to scheme (B), the hydrolysis of acyl groups, in particular acetyl groups, is carried out in the presence of water.

According to this embodiment of the process of the invention, commercially available enzymes having the above definitions can be used as the enzymes described above (e.g.CALB enzyme on a polymeric support derived from Candida antarctica, e.g.from SigmaAldrich or Merck), according to scheme (B)435 or from Strem Chemicals, Inc435)。

As mentioned above, according to the synthesis scheme (B), the compounds of general formula (Ib) as defined above are used as reactants. The compounds of general formula (Ib) as defined above are readily or conveniently available.

As far as the compounds of the general formula (Ib) defined above are used in the process according to the invention according to scheme (B), they are obtainable by reaction of a carboxylic anhydride of the general formula (V) with 3-hydroxybutyric acid,

R²-O-R²(V)

wherein the radical R²Having the meaning defined above, in particular acetic anhydride or propionic anhydride, preferably acetic anhydride.

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

wherein the radical R²Have the meaning defined above.

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

wherein the group Ac represents an acetyl group.

The temperature of the reaction of the carboxylic anhydride of the general formula (V) defined above with 3-hydroxybutyric acid may vary within wide limits. In particular, the reaction of the carboxylic anhydride of the general formula (V) as defined above with 3-hydroxybutyric acid may be carried out at a temperature in the range from 60 to 150 ℃, in particular in the range from 70 to 120 ℃, preferably in the range from 80 to 100 ℃.

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

According to a particular embodiment of the process of the invention according to scheme (B), the invention relates to a process for the production of fatty alcohol esters of 3-hydroxybutyric acid (beta-hydroxybutyric acid, BHB or 3-BHB) as defined above,

wherein, according to the synthetic route (B),

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

R²-O-R² (V)

wherein R is²Have the meaning defined above; and then subsequently

(b)In a second process step (b), the compound of general formula (Ib) as defined above thus obtained is reacted with a compound selected from C as defined above₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-at least one fatty alcohol (II) reaction of fatty alcohols; and then subsequently

(c) In a third process step (c), the acyl group is hydrolyzed,

thus obtaining C of 3-hydroxybutyric acid as reaction product (III)₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

As described above with respect to scheme (B), the reaction of at least one compound of general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above, carried out according to scheme (B), also leads to an acylation, in particular an acetylation or a 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 substituted by an acyl group, in particular acetyl-C (O) -CH₃Or propionyl-C (O) -C₂H₅Substitution). The reaction product obtained during the reaction of at least one compound of general formula (Ib) as defined above with at least one fatty alcohol (II) as defined above (═ reaction intermediate (IIIa)), can be isolated or isolated and the hydrolysis of the acyl group is not subsequently carried out.

Since, as mentioned above, the applicant has surprisingly found that the reaction intermediate (IIIa) formed according to scheme (B) prior to acyl hydrolysis, 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 of a salt thereof, and can therefore also be used in large amounts in medicine or in the clinic due to its physiological compatibility; these reaction intermediates therefore likewise represent physiologically and pharmacologically relevant substitutes for free 3-hydroxybutyric acid or its salts.

According to a particular embodiment according to scheme (B), C of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) can be obtained as reaction intermediate (IIIa) before hydrolysis of the acyl group, in particular the acetyl group₁₀-C₃₀Fatty alcohol esters, in particular acylC of 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated fatty C esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₃₀Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄-fatty alcohol esters.

According to another particular embodiment, according to scheme (B), it is possible to obtain, as reaction intermediate (IIIa), a compound derived from C before hydrolysis of the acyl group, in particular the acetyl group₁₀-C₃₀Carboxylic esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched C₁₀-C₂₄-carboxylic acid esters of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated fatty monoalcohols and preferably primary C₁₀-C₃₀The carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols are preferably derived from linear or branched, saturated or mono-or polyunsaturated aliphatic monoalcohols and preferably primary C₁₀-C₂₄Acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols.

In particular, herein, C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-fatty alcohols selected from the group consisting of 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans-oleyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol) and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

According to the invention, it is preferred in this case that the acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is acetylated 3-hydroxybutyrate (3-acetoxybutyrate).

According to a further particular embodiment according to scheme (B), the carboxylic acid ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) derived from linear, saturated or mono-or polyunsaturated aliphatic monobasic primary C can be obtained as reaction intermediate (IIIa) before the hydrolysis of the acyl group, in particular of the acetyl group₁₀-C₂₄A fatty alcohol.

Finally, according to another embodiment according to scheme (B), the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of general formula (IIIa) can be obtained as reaction intermediate (IIIa) before the hydrolysis of the acyl group, in particular the acetyl group,

CH₃-CH(OR²)-CH₂-C(O)OR³ (IIIa)

wherein, in the general formula (IIIa),

·R²represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group) and (C) in the presence of a water-soluble polymer,

·R³denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀Alkyl, preferably C₁₀-C₂₄-an alkyl group.

In particular, the group R in formula (IIIa)³May represent 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecyl (pearlo-lipidyl), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melissyl), cis-9-hexadecen-1-yl (palmityl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (trans-oleyl), cis-11-octadecen-1-yl, cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

Further description of the generality of the process of the invention, in particular according to scheme (A) and scheme (B)

All the following description relates to the process of the invention as a whole or in analogy, both scheme (a) and scheme (B) of the process of the invention.

Synthesis routes (A) and (B) according to the process of the invention, using a compound selected from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄Fatty alcohol (II) of fatty alcohol as a reactant.

According to one embodiment of the process of the invention, it may be provided in particular that the fatty alcohol (II) used in the process of the invention corresponds to the general formula (II'),

R³-OH (II’)

wherein the radical R³Denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-alkyl groups, in particular wherein the hydroxyl function (OH function) is primary and/or terminal.

In particular, preference is given in the context according to the invention to the group R in the formula (II'), (II)³Denotes linear, saturated or monounsaturated or polyunsaturated aliphatic C₁₀-C₂₄-an alkyl group; in particular hydroxyl functions (OH functions) are primary and/or terminal.

In particular, it is further preferred in the context according to the invention that in the general formula (II'), the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (gamma-linolenyl), preferably cis-9-octadecadien-1-ylEn-1-yl (oleyl).

In particular, the fatty alcohols (II) which can be used in the process of the invention can be chosen from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic C₁₀-C₃₀Fatty alcohols, especially C₁₀-≤C₂₄The fatty alcohols preferably have primary and/or terminal hydroxyl functions (OH functions).

According to one particular embodiment of the process of the invention, the fatty alcohol (II) may be chosen from linear, saturated or mono-unsaturated or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₃₀Fatty alcohols, in particular linear, saturated or monounsaturated or polyunsaturated aliphatic monohydric and preferably primary C₁₀-C₂₄A fatty alcohol.

According to another particular embodiment of the process of the invention, the fatty alcohol (II) may be chosen from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans-oleyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

The fatty alcohols (II) mentioned above are commercially available chemical products or are readily available elsewhere.

As regards the reaction products obtainable in the process of the invention, as described previously, as reaction product (III) of the process of the invention (according to scheme (A) and according to scheme (B)), C of 3-hydroxybutyric acid is obtained in each case₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

In particular, during the process of the invention, as reaction product (III), C of 3-hydroxybutyric acid may be obtained₁₀-C₃₀Esters of fatty alcohols, especially 3-hydroxybutylC of acids₁₀-C₂₄Linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of fatty alcohols, preferably of 3-hydroxybutyric acid₁₀-C₃₀Linear or branched, saturated or mono-or polyunsaturated aliphatic C esters of fatty alcohols, preferably of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters.

In particular, during the process of the invention, as reaction product (III), it is possible to obtain compounds derived from C₁₀-C₃₀Carboxylic esters of 3-hydroxybutyric acid of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C₁₀-C₃₀Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₂₄-3-hydroxybutyric acid carboxylate of fatty alcohol.

Within the scope of the process according to the invention, C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄-fatty alcohols selected from the group consisting of 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearly-lustre alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans-oleyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

According to a particular embodiment of the process of the invention, as reaction product (III), a fatty alcohol ester of 3-hydroxybutyric acid of general formula (III') is obtained,

CH₃-CH(OH)-CH₂-C(O)OR³ (III’)

wherein the radical R³Denotes linear or branched, saturated or monounsaturated or polyunsaturatedAliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-an alkyl group.

According to another embodiment of the process of the present invention, as reaction product (III), a fatty alcohol ester of 3-hydroxybutyric acid of the above-mentioned formula (III ') is obtained, wherein, in formula (III'), the radical R³Denotes linear, saturated or monounsaturated or polyunsaturated C₁₀-C₂₄An aliphatic alkyl group.

According to another embodiment of the process of the present invention, as reaction product (III), the fatty alcohol ester of 3-hydroxybutyric acid of formula (III ') above may be obtained, wherein, in formula (III'), the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl). .

As mentioned above, the Applicant has found, entirely surprisingly, that the above-mentioned reaction products obtained according to the process of the invention (i.e. the fatty alcohol esters of 3-hydroxybutyric acid) are effective, since physiologically compatible precursors and/or metabolites of 3-hydroxybutyric acid or of its salts may also be used in large quantities in medicine or in the clinic, since they are physiologically compatible; thus, these reaction products represent physiologically and pharmacologically relevant alternatives to free 3-hydroxybutyric acid or its salts.

Within the scope of the production process of the present invention, the reaction products and their formation, in particular the conversion and yield, and the selectivity can be controlled and/or regulated by the reaction conditions, in particular by the choice of the reaction temperature (conversion temperature) and/or of the reaction pressure (conversion pressure) and/or by the choice of the catalyst and its type and/or amount and/or by the choice of the amount of the starting compounds (reactants) and/or by the removal of by-products.

After the reaction, the reaction product obtained may be subjected to further purification or work-up steps which are customary or known per se.

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

Furthermore, according to the invention, unreacted starting compounds (Ia) or (Ib) and/or (II) can be isolated from the reaction product (III) and/or (in the case of synthesis scheme (B)) from the reaction intermediate (IIIa) and subsequently recycled. Such a process may improve process economics, particularly in the case of large scale or industrial implementation.

Preferred processes according to scheme (A) and according to scheme (B) according to the invention are illustrated by the following reactions or synthetic schemes (wherein the compounds (Ia), (Ib), (II), (III/III') and (IIIa) each have the meaning defined above, including the group R used therein¹，R²And R³)：

According to a second aspect of the invention, another subject is the reaction product obtainable according to the process of the invention (as indicated above) or the reaction product of the invention (i.e.C of 3-hydroxybutyric acid)₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-fatty alcohol esters). In particular, the reaction products according to the invention can be obtained by synthetic route (a) and/or synthetic route (B).

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 a reaction product as defined above (i.e. a fatty alcohol ester obtainable according to the inventive process described above or a fatty alcohol ester of the invention), wherein the fatty alcohol ester of 3-hydroxybutyric acid is the C-ester of 3-hydroxybutyric acid₁₀-C₃₀Fatty alcohol esters, in particular C of 3-hydroxybutyric acid₁₀-C₂₄-estersFatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated fatty C esters of 3-hydroxybutyric acid₁₀-C₃₀Fatty alcohol esters, preferably linear or branched, saturated or mono-or polyunsaturated fatty C esters of 3-hydroxybutyric acid₁₀-C₂₄A fatty alcohol ester.

According to a particular embodiment according to this aspect of the invention, the object of the invention is a fatty alcohol ester of 3-hydroxybutyric acid, in particular as defined above, in particular a reaction product as defined above, wherein the fatty alcohol ester of 3-hydroxybutyric acid is derived from C₁₀-C₃₀Carboxylic esters of 3-hydroxybutyric acid of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated C₁₀-C₃₀Carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols, preferably derived from linear or branched, saturated or monounsaturated or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₂₄-carboxylic acid esters of 3-hydroxybutyric acid of fatty alcohols.

In this context, the C from which the above-described fatty alcohol ester of 3-hydroxybutyric acid of the present invention is derived₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄Fatty alcohols, preferably chosen from the group 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (pearlitic alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignocenol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (myricyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (elaidyl alcohol), cis-11-octadecen-1-ol, Cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

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

CH₃-CH(OH)-CH₂-C(O)OR³ (III’)

wherein the radical R³Denotes linear or branched, saturated or mono-or polyunsaturated aliphatic C₁₀-C₃₀-alkyl groups, preferably C₁₀-C₂₄-an alkyl group.

According to the invention, particular preference is given in this context to the fact that in the formula (III'), the radical R³Denotes linear, saturated or monounsaturated or polyunsaturated aliphatic C₁₀-C₂₄-an alkyl group.

According to the invention, it is also particularly preferred in this context that, in the formula (III'), the radical R³Represents 1-decyl group, 1-dodecyl group (lauryl group), 1-tetradecyl group (myristyl group), 1-hexadecyl group (cetyl group), 1-heptadecyl group (pearlyl group), 1-octadecyl group (stearyl group), 1-eicosyl group (arachidyl group), 1-docosyl group (behenyl group), 1-tetracosyl group (lignoceryl group), 1-hexacosyl group (ceryl group), 1-octacosyl group (montanyl group), 1-triacontyl group (melissiyl group), cis-9-hexadecen-1-yl group (palmityl group), cis-9-octadecen-1-yl group (oleyl group), trans-9-octadecen-1-yl group (trans-oleyl group), cis-11-octadecen-1-yl group, cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

As previously mentioned, the applicant has found, entirely surprisingly, that the reaction intermediate formed according to scheme (B) before the hydrolysis of the acyl group, i.e. the fatty alcohol ester of acylated 3-hydroxybutyric acid or, synonymously, of 3-acyloxybutyric acid, is effective, since physiologically compatible precursors and/or metabolites of 3-hydroxybutyric acid or of its salts, due to their physiological compatibility, can also be used in large quantities in medicine or in clinics; thus, this reaction intermediate also represents a physiologically and pharmacologically relevant substitute for free 3-hydroxybutyric acid or its salts.

Therefore, according to a second aspect of the present invention, the present invention also aims at a reaction intermediate, in particular a (chemical) product, in particular reaction intermediate (IIIa), according to a particular embodiment, preferably an aliphatic alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid), obtainable according to the process defined above, according to scheme (B) before the hydrolysis of the acyl group.

According to this embodiment, the subject of the present invention is in particular a fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid), in particular a reaction intermediate as defined above, wherein the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is the C of acylated 3-hydroxybutyrate (3-acyloxybutyric acid)₁₀-C₃₀Esters of fatty alcohols, in particular acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄Fatty alcohol esters, preferably acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) linear or branched C₁₀-C₃₀Esters of saturated or monounsaturated or polyunsaturated aliphatic fatty acids, preferably linear or branched, saturated or monounsaturated or polyunsaturated C acylated 3-hydroxybutyric acid (3-acyloxybutyric acid)₁₀-C₂₄-an aliphatic fatty alcohol ester.

In particular, according to this particular embodiment, the object of the present invention is a fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid), in particular as defined above, in particular a reaction intermediate as defined above, wherein the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is derived from C₁₀-C₃₀Carboxylic esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, in particular derived from C₁₀-C₂₄-carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols, preferably derived from linear or branched, saturated or mono-or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₃₀The carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols are preferably derived from linear or branched, saturated or mono-or polyunsaturated aliphatic mono-and preferably primary C₁₀-C₂₄Acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) carboxylic acid esters of fatty alcohols.

In this context, it is particularly preferred according to the invention if the above-mentioned fatty alcohol ester of acylated 3-hydroxybutyric acid of the invention is derived from C₁₀-C₃₀Fatty alcohols, especially C₁₀-C₂₄The fatty alcohol is selected from 1-decanol, 1-dodecanol (lauryl alcohol), 1-tetradecanol (myristyl alcohol), 1-hexadecanol (cetyl alcohol), 1-heptadecanol (nacreol alcohol), 1-octadecanol (stearyl alcohol), 1-eicosanol (arachidyl alcohol), 1-docosanol (behenyl alcohol), 1-tetracosanol (lignoceryl alcohol), 1-hexacosanol (ceryl alcohol), 1-octacosanol (montanyl alcohol), 1-triacontanol (melissyl alcohol), cis-9-hexadecen-1-ol (palmitoleyl alcohol), cis-9-octadecen-1-ol (oleyl alcohol), trans-9-octadecen-1-ol (trans-oleyl alcohol), cis-11-octadecen-1-ol, and cis, cis-9, 12-octadecadien-1-ol (linoleol), 6,9, 12-octadecatrien-1-ol (γ -linolenol), and combinations thereof, preferably cis-9-octadecen-1-ol (oleyl alcohol).

According to the invention, it is preferred in this case that the acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is acetylated 3-hydroxybutyrate (3-acetoxybutyrate).

In particular, according to this particular embodiment, the present invention also aims at acylating a fatty alcohol ester of 3-hydroxybutyric acid (3-acyloxybutyric acid), in particular as defined above, in particular a reaction intermediate as defined above, wherein the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) is derived from a linear, saturated or mono-or polyunsaturated aliphatic, monohydric primary C, ester₁₀-C₂₄Carboxylic acid esters of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of fatty alcohols.

Finally, according to this embodiment, the present invention also has for its object the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid), in particular as defined above, in particular the reaction intermediate as defined above, wherein the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) is a fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) of general formula (IIIa),

CH₃-CH(OR²)-CH₂-C(O)OR³ (IIIa)

wherein, in the general formula (IIIa),

·R²represents a group selected from-C (O) -CH₃(acetyl) or-C (O) -C₂H₅(propionyl) acyl, preferably-C (O) -CH₃(acetyl group) and (C) in the presence of a water-soluble polymer,

·R³represents a linear or branched, saturated or monounsaturated or polyunsaturated aliphatic C₁₀-C₃₀-alkyl, preferably C₁₀-C₂₄-an alkyl group.

In particular, the radical R³May represent 1-decyl, 1-dodecyl (lauryl), 1-tetradecyl (myristyl), 1-hexadecyl (cetyl), 1-heptadecyl (pearlo-lipidyl), 1-octadecyl (stearyl), 1-eicosyl (arachidyl), 1-docosyl (behenyl), 1-tetracosyl (lignoceryl), 1-hexacosyl (ceryl), 1-octacosyl (montanyl), 1-triacontyl (melissyl), cis-9-hexadecen-1-yl (palmityl), cis-9-octadecen-1-yl (oleyl), trans-9-octadecen-1-yl (trans-oleyl), cis-11-octadecen-1-yl, cis, cis-9, 12-octadecadien-1-yl (linoleyl) or 6,9, 12-octadecatrien-1-yl (γ -linolenyl), preferably cis-9-octadecen-1-yl (oleyl).

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-hydroxybutyrate as defined above, respectively as defined above, or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) as defined above obtainable according to the production process of the invention (i.e. the intermediate reaction product prior to hydrolysis according to scheme (B)), or the fatty alcohol ester of 3-hydroxybutyrate as defined above of the invention and the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) as defined above, respectively, have a number of advantages and special features compared to the prior art:

as the applicants have surprisingly found that the reaction product obtainable according to the process of the invention or the reaction product according to the invention, respectively, as defined above, and/or the fatty alcohol ester of 3-hydroxybutyric acid or the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid), as defined above, obtainable according to the production process of 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), as defined above, of the invention, are suitable as precursors or metabolites, respectively, of 3-hydroxybutyric acid or salts thereof, respectively, since on the one hand these compounds are converted into 3-hydroxybutyric acid or salts thereof physiologically, in particular in the gastrointestinal tract, and on the other hand they simultaneously have a good physiological compatibility or tolerance, particularly in terms of non-toxicity and acceptable organoleptic properties.

Furthermore, the reaction product obtainable according to the process of the invention or the reaction product of the invention, respectively, 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, of the invention, are readily available or are available on a large scale, even a commercial scale on a synthetic basis, and have the desired pharmaceutical or pharmacological quality.

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, respectively 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, may be provided, if necessary, in enantiomerically pure or enantiomerically enriched form, respectively.

The reaction product obtainable according to the process of the invention or the reaction product of the invention, respectively, as defined above, and/or the fatty alcohol ester of 3-hydroxybutyrate, as defined above, obtainable according to the production process of the invention, and the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid), as defined above, or the fatty alcohol ester of 3-hydroxybutyrate, as defined above, and the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid), as defined above, of the invention, thus represent effective pharmacological drug targets in the context of ketone body therapy of the human or animal body, respectively.

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

According to a third aspect of the present invention, another subject of the present invention is a pharmaceutical composition, in particular a medicament (pharmaceutical product) or pharmaceutical agent, comprising the reaction product obtainable according to the production process of the present invention or the reaction product of the present 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, as intermediate reaction product before hydrolysis according to synthetic route (B), respectively.

In particular, according to this aspect of the invention, the invention relates to a pharmaceutical composition for use in the prophylactic and/or therapeutic treatment or for use in the prophylactic and/or therapeutic treatment of a disease of the human or animal body. This may in particular relate to diseases associated with disorders of 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 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 sphingolipid disorders, in particular niemann-pick's disease, the effects or side effects of diabetes and chemotherapy.

Likewise, according to a fourth aspect of the present invention, a further subject-matter of the present invention is the reaction product obtainable according to the production process of the present invention or the reaction product of the present invention, respectively, as defined above, or the fatty alcohol ester of 3-hydroxybutyric acid and/or the fatty alcohol ester of acylated 3-hydroxybutyric acid (3-acyloxybutyric acid) of the present invention, as defined above, obtainable according to the production process of the present invention, for use in the prophylactic and/or therapeutic treatment or for the prophylactic and/or therapeutic treatment of a disease of the human or animal body, in particular a disease associated with a disturbance of energy metabolism, in particular of 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, disorders of fat metabolism such as glucose transport defects (defects of GLUT 1), VL-FAOD and mitochondrial diseases such as defects of mitochondrial thiolase, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and uricosurthritis, gastrointestinal diseases such as chronic inflammatory bowel disease, in particular ulcerative colitis and Crohn's disease, lysosomal storage diseases such as sphingolipid disorders, in particular Niemann-pick disease, the effects or side effects of diabetes and chemotherapy.

Likewise, according to a fifth aspect of the present invention, another subject of the present invention is the use of a reaction product obtainable according to the production process of the present invention or a reaction product of the present 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, of the present invention, for the prophylactic and/or therapeutic treatment, or for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of a disease of the human or animal body, in particular of a disease associated with energy metabolism, In particular disorders of 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, disorders of fat metabolism 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 sphingolipid diseases, in particular Niemann-pick disease, diabetes and the effects or side effects of chemotherapy.

Also according to a sixth aspect of the invention, another subject of the invention is the reaction product obtainable according to the production process of the invention or the reaction product of 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 according to the production process of the present 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 use in prophylactic and/or therapeutic treatment, or for the manufacture of a medicament for prophylactic and/or therapeutic treatment or for use in catabolic states (e.g. starvation, diet or low carbohydrate nutrition).

Likewise, according to a seventh aspect of the present invention, another subject of the present invention is a food and/or foodstuff comprising the reaction product obtainable according to the production process of the present invention or the reaction product of the present invention, respectively, as defined above, or the fatty alcohol ester of 3-hydroxybutyrate as defined above and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) as defined above, obtainable according to the production process of the present invention, or the fatty alcohol ester of 3-hydroxybutyrate as defined above and/or the fatty alcohol ester of acylated 3-hydroxybutyrate (3-acyloxybutyric acid) as defined above.

According to a particular embodiment, the food and/or food product may be essentially a dietary supplement, a functional food, a novel food, a food additive, a food supplement, a dietary food, an energy treat, an appetite suppressant or a strength and/or endurance exercise supplement.

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

According to this aspect of the invention, the food and/or foodstuff 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 exercise supplement.

Further embodiments, modifications, and variations of the present invention may be readily identified or implemented by those of ordinary skill in the art upon reading the present specification without departing from the scope of the present invention.

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

Example (b):

abbreviations used

3-BHB-Ethyl ═ 3-hydroxybutanoic acid ethyl ester

3-BHB-decyl ═ 3-hydroxybutyric decyl ester

3-BHB-oleyl ═ 3-hydroxybutyric acid oleyl ester

Dimer, dimer of 3-hydroxybutyric acid and/or ethyl 3-hydroxybutyrate (reaction by-product).

Production examples

The production process according to the invention is illustrated by the following examples. The general reaction scheme therefor is shown and explained in the general description section.

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

In a 500ml multi-neck flask with a fractionator (partial condenser) and a distillation bridge, 132g of ethyl (R)/(S) -3-hydroxybutyrate, 158g of 1-decanol and 2.9g of immobilized enzyme (CALB enzyme on a polymeric support, from Candida antarctica, e.g.from Sigma Aldrich or Merck) are provided435 or from Strem Chemicals, Inc435)。

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

Production of 3-BHB-oleyl ester according to synthetic route (A)

In a 500ml multi-neck flask with a fractionator (partial condenser) and a distillation bridge, 132g of ethyl (R)/(S) -3-hydroxybutyrate, 270g of oleyl alcohol (purity: 85%) and 4.0g of immobilized enzyme (CALB enzyme on polymer carrier, from Candida antarctica, e.g.from Sigma Aldrich or Merck) are provided435 or from Strem Chemicals, Inc435)。

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

Table:conversion/time-series for the preparation of 3-BHB-oleyl esterLine (50 ℃, 50-60 mbar, 24 hours, 1 wt% enzyme).

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

The enzymatic synthesis described above was also carried out using other fatty alcohols (i.e., cetyl alcohol, pearlyl alcohol, stearyl alcohol, behenyl alcohol, myricyl alcohol, palmitoleyl alcohol, and linoleyl alcohol). The corresponding 3-BHB fatty alcohol esters were obtained in each case as pure substances.

Further producing 3-BHB fatty alcohol ester according to the synthetic route (A)

However, when the previous experiment was repeated, with sodium methoxide (NaOMe) as catalyst (1% by weight) instead of enzyme, 40 mol% excess of 3-BHB ethyl ester, the temperature was between 100 and 120 ℃. Comparable results were obtained. Purification and isolation were performed in the same manner.

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

1. The method comprises the following steps: synthesis of acetylated 3-BHB anhydride

In a 1000ml multi-neck flask with a fractionator (partial condenser) and a distillation bridge, 25g of (R)/(S) -3-hydroxybutyric acid in 95g of acetic acid was provided. 90g of acetic anhydride were added to the reaction mixture over one hour at 80 ℃ under a nitrogen atmosphere. The reaction mixture was further stirred at 80 ℃ for 4 to 5 hours. 3-acetoxybutyric anhydride (acetylated 3-hydroxybutyric anhydride) is formed.

2. The method comprises the following steps: reaction of acetylated 3-BHB anhydride with fatty alcohol

Then, 30g of 1-decanol was added to the reaction mixture at 80 ℃ 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 the production of the corresponding fatty alcohol ester of 3-BHB, but is itself pharmaceutically applicable or effective for the same intended use.

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

3. The method comprises the following steps: enzymatic hydrolysis of acetyl groups

Part of the intermediate product of the second step (i.e. the fatty alcohol 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 immobilized on an enzyme (CALB enzyme on a polymer support, from Candida antarctica, first preparation: from Sigma Aldrich or Merck)435, second formulation: from Strem Chemicals, Inc435) In the presence of water at 50 ℃ for 8 hours. After enzymatic separation and subsequent purification by distillation, fatty alcohol 3-hydroxybutyrate is obtained as the hydrolysis product, decyl 3-hydroxybutyrate. Characterization was performed by GC, GPC and GC-MS.

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

Further producing 3-BHB decyl ester according to the synthetic route (B)

However, the previous experiment was repeated, after the reaction of (R)/(S) 3-hydroxybutyrate anhydride, the by-product (acetic acid) formed in the first step was first removed by distillation at 100 to 120 ℃ and vacuum (<50mbar) to give pure 3-acetoxybutyrate anhydride. Characterization was performed by GC, GPC and GC-MS.

Pure 3-acetoxybutyric anhydride was then reacted with 1-decanol, purified and analyzed (as described in previous experiments) to give pure fatty ester of 3-acetoxybutyric acid.

The reaction product (i.e., the fatty alcohol ester of 3-acetoxybutyric acid) was then hydrolyzed as described in the previous experiment to yield the fatty alcohol ester of 3-hydroxybutyric acid, i.e., decyl 3-hydroxybutyrate. Characterization was performed by GC, GPC and GC-MS.

Production of 3-BHB oil esters according to synthetic route (B)

1. The method comprises the following steps: synthesis of acetylated 3-BHB anhydride

In a 1000ml multi-neck flask with a fractionator (partial condenser) and a distillation bridge, 25g of (R)/(S) -3-hydroxybutyric acid in 95g of acetic acid was provided. Then 90g of acetic anhydride were added to the reaction mixture over the course of one hour at 80 ℃ under a nitrogen atmosphere. The reaction mixture was further stirred at 80 ℃ for 4 to 5 hours. 3-acetoxybutyric anhydride (acetylated 3-hydroxybutyric anhydride) is formed.

2. The method comprises the following steps: reaction of acetylated 3-BHB anhydride with fatty alcohol

Subsequently 52g of oleyl alcohol were added to the reaction mixture at 80 ℃ 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., an oleyl ester of acetylated 3-hydroxybutyric acid) and an intermediate for the preparation of the corresponding fatty alcohol ester of 3-BHB, but is itself pharmaceutically acceptable or effective for the same purpose.

The by-products (acetic acid from the first step and 3-acetoxybutyric acid from the second step) were distilled under vacuum (<50mbar) at 100 to 120 ℃ to give pure fatty alcohol ester of 3-acetoxybutyric acid. Characterization was performed by GC, GPC and GC-MS.

3. The method comprises the following steps: enzymatic hydrolysis of acetyl groups

Part of the intermediate from the second step (i.e. the oleyl ester of 3-acetoxybutyric acid) is subsequently subjected to hydrolysis (partial or selective hydrolysis in the presence of an enzyme) of the acetyl group. For this purpose, the reaction product of the second step is immobilized on an enzyme (CALB enzyme on a polymer support, from Candida antarctica, first preparation: from Sigma Aldrich or Merck)435, second formulation: from Strem Chemicals, Inc435) The reaction was carried out in an aqueous medium at 50 ℃ for 8 hours in the presence of a catalyst. After enzymatic separation and subsequent purification by distillation, the fatty alcohol ester of 3-hydroxybutyric acid, i.e. the oil ester of 3-hydroxybutyric acid, is obtained as a hydrolysis product. Characterization was performed by GC, GPC and GC-MS.

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

Further producing 3-BHB oil ester according to the synthetic route (B)

The previous experiment was repeated, however, after the reaction of (R)/(S) 3-hydroxybutyrate anhydride the by-product (acetic acid) formed in the first step was first removed by distillation at 100 to 120 ℃ under vacuum (<50mbar) and pure 3-acetoxybutyrate anhydride was obtained. Characterization was performed by GC, GPC and GC-MS.

Pure 3-acetoxybutyric anhydride was then reacted with oleyl alcohol, purified and analyzed (as described in previous experiments) to yield pure fatty ester of 3-acetoxybutyric acid.

The reaction product (i.e., the oleyl ester of 3-acetoxybutyric acid) was then hydrolyzed as described in the previous experiment to give the oleyl ester of 3-hydroxybutyric acid, i.e., the oleyl ester of 3-hydroxybutyric acid. Characterization was performed by GC, GPC and GC-MS.

Further producing 3-BHB fatty acid ester according to the synthetic route (B)

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

In the first series of preparations, sulfuric acid (H) was used as catalyst₂SO₄) Repeating the reaction of 1-decanol and oleyl alcohol in the presence of (a) at a temperature of between 75 and 110 ℃. Comparable results were obtained. Purification, separation or fractionation and hydrolysis are carried out in the same manner.

In a second series of preparations, the reaction of 1-decanol and oleyl alcohol was repeated at a temperature between 75 and 110 ℃ in the presence of hydrochloric acid (HCl) as catalyst, respectively. Comparable results were obtained. Purification, separation or fractionation and hydrolysis are carried out in the same manner.

In the third series of preparations, phosphoric acid (H) as catalyst was added₃PO₄) Repeating the reaction of 1-decanol and oleyl alcohol in the presence of (a) at a temperature between 75 and 110 ℃. Comparable results were obtained. Purification, separation or fractionation and hydrolysis are carried out in the same manner.

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

The above synthesis (autocatalytic and mineral acid catalyzed) was also carried out correspondingly for other fatty alcohols (i.e. for cetyl alcohol, pearlitic alcohol, stearyl alcohol, behenyl alcohol, melissyl alcohol, palmitolein alcohol and linoleyl alcohol, respectively). The corresponding 3-BHB fatty alcohol esters were obtained in each case as pure substances.

Physiological application test: in vitro digestion test

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

It has been shown by cleavage experiments that 3-BHB-PG (2) esters prepared according to the present invention or mixtures thereof, including reaction by-products such as dimers and the like, can be cleaved in the human gastrointestinal tract.

The test substance used is, on the one hand, a purified 3-BHB fatty alcohol ester obtained by the process according to the invention (i.e. obtained by the process according to scheme (a) and the process according to scheme (B)), and, on the other hand, a pure acetylated 3-BHB (3-acetylbutanoic acid) fatty alcohol ester obtained by the process according to the invention, as reaction intermediate according to scheme (B).

Fatty alcohol esters tested:

3-BHB decyl ester

Acetylated 3-BHB decyl ester (3-acetoxybutyric decyl ester)

3-BHB oil ester

Acetylated 3-BHB oleyl ester (oleyl ester of 3-acetoxybutyric acid)

3-BHB cetyl ester

3-BHB pearlescent tallow ester

3-BHB stearate

3-BHB behenate

3-BHB Melissyl ester

3-BHB palm oil ester

3-BHB linoleate

Lysis experiments were studied for both media under similar body conditions:

FaSSGF, gastric mimic

FaSSIF, simulation of intestinal tract

Both media are from BritishLtd. In addition, porcine pancreas was added to both media in some experiments: (40,000,Fa.Allergan)。

In useAnd is not usedThe results of lysis experiments in the FaSSGF or FaSSIF medium (both 35 ℃ C., 24 hours) show that the samples are in useAnd is not usedHydrolysis under FaSSGF conditions; this is mainly due to the low pH of the medium (pH 1.6). Under FaSSIF conditions, useThe conversion of (3) is low.

Further digestion experiments (cracking experiments) of the 3-BHB fatty alcohol ester of the invention (i.e., the fatty alcohol ester of 3-hydroxybutyric acid)

Cleavage experiments with pancreatin

In each case 2g of fatty alcohol 3-hydroxybutyrate or acetylated derivative thereof prepared as described above (i.e. obtained by a process according to scheme (a) and a process according to scheme (B)) are dissolved in 50g of water and 0.5g (1 wt%) of pancreatin are added. Pancreatin as a commercially available product from Allergan40,000 in form. The whole mixture was stirred on a hot plate at 50 ℃; the course of the reaction was determined and monitored by continuously recording the acid number over time. Acid value is in the same scaleThe duration of the observation increased (3-BHB fatty alcohol ester or acyl derivative thereof cleaved to the free acid). The conversion/time course of the ester mixture according to the invention by water-splitting of pancreatin, including the increase in acid number over time, proves to be a satisfactory decomposition of the educt mixture into the free acid. Appropriate analysis confirmed this. It was experimentally demonstrated that the fatty alcohol esters of 3-hydroxybutyric acid or acetylated derivatives thereof according to the present invention, i.e. obtained by the method according to scheme (a) and the method according to scheme (B), are suitable physiological precursors of 3-hydroxybutyric acid for use in the corresponding ketone body therapy.

The cleavage experiments described previously demonstrated that fatty alcohol esters of 3-hydroxybutyric acid or acyl derivatives thereof are effective precursors or metabolites of free hydroxybutyric acid or its salts, especially in a physiologically compatible form with respect to their intended effect.