Method for producing lipids comprising structural units based on glycerides of hydroxycarboxylic acids

文档序号：54060 发布日期：2021-09-28 浏览：39次中文

阅读说明：本技术 生产包含基于羟基羧酸的甘油酯的结构单元的脂质的方法 (Method for producing lipids comprising structural units based on glycerides 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：本发明涉及生产包含基于3-羟基丁酸和/或3-烷氧基丁酸的甘油酯的结构单元的脂质的方法以及由此获得的产物和它们的用途。(The present invention relates to a process for producing lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, as well as to the products thus obtained and to their uses.)

1. A method for producing a lipid comprising a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid,

wherein at least one glyceride of the general formula (I)

R¹O-CH₂-CH(OR²)-CH₂-OR³ (I)

Wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

The presence of hydrogen in the gas phase,

a radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R¹、R²And R³At least one, preferably at least two, of which do not represent hydrogen,

with at least one 3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivative of formula (II)

CH₃-CH(OR⁴)-CH₂-C(O)OR⁵ (II)

Wherein in the general formula (II)

The radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

the radical R⁵Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄Alkyl, preferably methyl or ethyl, more preferably ethyl,

thus, as reaction product, one or more lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid of general formula (III) are obtained

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Having the meaning as defined above, and which,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

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

wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

The presence of hydrogen in the gas phase,

linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -,

linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R¹、R²And R³At least one, preferably at least two of (a) do not represent hydrogen.

3. The method of claim 1 or claim 2,

wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

Linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -,

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

wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

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

wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

provided, however, that the group R¹、R²And R³At least one of them represents a linear (linear) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

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

wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

provided, however, that the group R¹、R²And R³At least one of them represents a linear (linear) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -, and with the proviso that the radical R¹、R²And R³At least one of them represents a linear (linear) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

7. The method of any one of claims 1 to 5,

wherein in the general formula (I), the radical R¹、R²And R³Identical or different, each independently of the others, represents a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁alkyl-C (O) -, in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -.

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

wherein in the general formula (I), the radical R¹、R²And R³Identical or different, each independently of the others, represents a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branchedChain, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

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

wherein in the general formula (II)

The radical R⁴Represents hydrogen or a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₃₀Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₂₁alkyl-C (O) -, preferably linear (linear) or branched, saturated or mono-or polyunsaturated C₃-C₂₁-alkyl-C (O) -,

the radical R⁵Represents C₁-C₄Alkyl, especially C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl.

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

wherein in the general formula (II)

the radical R⁵Represents an ethyl group.

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

wherein in the general formula (II), the radical R⁴Represents hydrogen, a radical R⁵Represents an ethyl group; and/or

Wherein, as 3-hydroxy-and/or 3-alkoxybutanoic acid derivatives of the general formula (II), use is made of the formula CH₃-CH(OH)-CH₂-C(O)OC₂H₅Ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate).

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

wherein the 3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivatives of general formula (II) may be used in the form of the racemate or in the form of the (R) enantiomer;

in particular wherein the (R) -configuration is based on a carbon atom in position 3 and/OR in particular wherein the (R) -configuration is based on a compound carrying OR⁴Carbon atoms of the group.

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

wherein the reaction is carried out in the absence of a solvent and/or in the absence of any solvent; and/or

Wherein 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; especially wherein the catalyst is recycled after the reaction.

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

wherein the reaction is carried out in the presence of an enzyme as a catalyst;

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 derived from candida antarctica, mucor miehei (rhizomucor miehei), thermomyces lanuginosus, candida rugosa, aspergillus oryzae, pseudomonas cepacia, pseudomonas fluorescens, rhizopus delbrueckii, and pseudomonas, and combinations thereof, preferably from candida antarctica, mucor miehei (rhizomucor miehei), and thermomyces lanuginosus; and/or

In particular wherein the enzyme is used in immobilized form, in particular immobilized 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; and/or

In particular wherein the enzyme is recycled after the reaction; and/or

In particular wherein the reaction is carried out in the presence of an enzyme as catalyst 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 ℃, even more preferably in the range of from 50 ℃ to 70 ℃; 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 starting compounds (I) and (II); and/or

In particular wherein the reaction is carried out in the presence of an enzyme as catalyst 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.

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

wherein the reaction is carried out in the presence of a metal-and/or metal-based acidic or basic catalyst;

in particular wherein 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, for example NaOH, KOH, LiOH, Ca (OH)₂NaOMe, KOMe and sodium tert-butoxide, (ii) acidic catalysts, especially mineral acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) lewis acids, especially those based on titanium, tin, zinc and aluminum compounds, such as tetrabutyl titanate, stannic acid, zinc acetate, aluminum trichloride and triisopropylaluminum, and (iv) heterogeneous catalysts, especially those based on mineral silicates, germanates, carbonates and aluminas, such as zeolites, montmorillonites, mordenite, hydrotalcite and alumina, and combinations thereof; and/or

In particular wherein alkali metal or alkaline earth metal alcoholates are used as catalyst; and/or

In particular, the catalyst is recycled after the reaction; and/or

In particular wherein the reaction is carried out in the presence of a metal-and/or metal-based acidic or basic catalyst 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 ℃, even more preferably in the range of from 100 ℃ to 120 ℃; and/or

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

In particular wherein the reaction is carried out in the presence of a metal-containing and/or metal-based acidic or basic catalyst at a pressure in the range of 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.

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

wherein, in the general formula (I), the group R¹、R²And R³At least one of which represents a group C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁In the case of alkyl-C (O) -and the radical R¹、R²And R³At least one of which represents a group C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -, the glycerides of formula (I) being obtainable or obtained by suitable transesterification.

17. The method of claim 16, wherein the first and second light sources are selected from the group consisting of,

wherein the transesterification is carried out by reacting under transesterification conditions at least one compound R of the formula (Ia)⁹O-CH₂-CH(OR¹⁰)-CH₂-OR¹¹ (Ia)

Wherein in the general formula (Ia), the radical R⁹、R¹⁰And R¹¹Same or different, eachIndependently represent

The presence of hydrogen in the gas phase,

a radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that there are at least two and preferably groups R⁹、R¹⁰And R¹¹And does not represent hydrogen, and is not,

with at least one compound of the formula (Ib)

R¹²O-CH₂-CH(OR¹³)-CH₂-OR¹⁴ (Ib)

Wherein in the general formula (Ib) the radical R¹²、R¹³And R¹⁴The same or different, each independently represent

The presence of hydrogen in the gas phase,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that there are at least two and preferably groups R¹²、R¹³And R¹⁴And does not represent hydrogen, and is not,

or (vice versa)

At least one compound of formula (Ib) as defined above is reacted with at least one compound of formula (Ia) as defined above under transesterification conditions.

18. The method according to claim 17, wherein said step of treating,

wherein in the general formula (Ia), the radical R⁹、R¹⁰And R¹¹Identical or different, each independently of the others, represents a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-c (o) -; and/or

Wherein in the general formula (Ib) the radical R¹²、R¹³And R¹⁴Identical or different, independently of one another, represent a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -and in particular linear (straight-chain) or branched, saturated or unsaturatedMono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

19. The method according to claim 17 or 18,

wherein, in the general formula (Ia), the group R⁹、R¹⁰And R¹¹In the case where one represents hydrogen, the compound of formula (Ia) is obtainable and/or obtained by partial hydrolysis, in particular partial (selective) enzymatic catalytic hydrolysis, of the corresponding starting triglyceride of formula (Ia) in which the group R⁹、R¹⁰And R¹¹None represent hydrogen and/or wherein the group R⁹、R¹⁰And R¹¹Identical or different, each independently of the others, represents a group C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-c (o) -; and/or

Wherein, in the general formula (Ib), the group R¹²、R¹³And R¹⁴In the case where one represents hydrogen, the compounds of the general formula (Ib) in which the radical R represents hydrogen can be obtained and/or obtained by partial hydrolysis, in particular partial (selective) enzymatic catalysis of the corresponding starting triglyceride of the general formula (Ib)¹²、R¹³And R¹⁴None represent hydrogen and/or wherein the group R¹²、R¹³And R¹⁴Identical or different, each independently of the others, represents a group C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -.

20. The method of any one of claims 16 to 19,

wherein the transesterification is carried out enzymatically.

21. The method of any one of claims 16 to 20,

wherein the transesterification is carried out in the presence of an enzyme as catalyst;

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 derived from candida antarctica, mucor miehei (mucor miehei), thermomyces lanuginosus, candida rugosa, aspergillus oryzae, pseudomonas cepacia, pseudomonas fluorescens, rhizopus delbrueckii, and pseudomonas, and combinations thereof, preferably from candida antarctica, mucor miehei (mucor miehei), and thermomyces lanuginosus; and/or

In particular wherein the enzyme is recycled after transesterification; and/or

In particular wherein the transesterification is carried out in the presence of an enzyme as catalyst 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 ℃, even more preferably in the range of from 50 ℃ to 70 ℃; and/or

In particular wherein the enzyme may be 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 (Ib); and/or

In particular wherein the transesterification is carried out in the presence of an enzyme as catalyst 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.

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

wherein, in the general formula (II), the group R⁴Is a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁In the case of alkyl-C (O) -3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivatives of general formula (II) may be obtained or obtained by reacting compounds of general formula (IV) below

CH₃-CH(OH)-CH₂-C(O)OR⁵ (IV)

Wherein in the general formula (IV), the radical R⁵Has the meaning defined hereinbefore, especially represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄-an alkyl group, preferably a methyl or ethyl group, more preferably an ethyl group,

with at least one carboxylic anhydride of the formula (V)

R¹⁵-C(O)-O-C(O)-R¹⁶ (V)

Wherein in the general formula (V), the group R¹⁵And R¹⁶Identical or different, each independently of the others, represents a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

at R⁵Optionally followed by hydrolysis in the presence of hydrogen;

in particular, the reaction of at least one compound of the formula (IV) with at least one carboxylic anhydride of the formula (V) can 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 ℃; and/or

In particular wherein the reaction of the at least one compound of the formula (IV) with the at least one carboxylic anhydride of the formula (V) can be carried out 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, very particularly at about 1 bar; and/or

In particular wherein the compound of the formula (VI) is reacted during the reaction of at least one compound of the formula (IV) with at least one carboxylic anhydride of the formula (V)

R¹⁷-C(O)-OH (VI)

Are formed simultaneously, wherein the radicals R¹⁷Represents a group R each having the meaning defined above¹⁵Or R¹⁶In particular, wherein the compound according to formula (VI) is removed during or after the reaction has taken place, in particular after the reaction has taken place, preferably by distillation.

23. The method of claim 22, wherein the first and second portions are selected from the group consisting of,

wherein, in the general formula (V), the group R¹⁵And R¹⁶In the case of being different from each other, and/or the radical R in the formula (V)¹⁵，R¹⁶In the case where each represents an alkyl group having more than two carbon atoms, the carboxylic anhydride of formula (V) can be obtained and/or obtained by reaction of acetic anhydride (acetic anhydride) with at least one carboxylic acid of formula (VII)

R¹⁸-C(O)-OH (VII)

Wherein the radical R¹⁸Represents a group R¹⁵Or R¹⁶Each having the meaning as defined above, provided, however, that the group R¹⁵And R¹⁶Different from each other and/or the group R¹⁵And R¹⁶The same or different, each independently represents an alkyl group having two or more carbon atoms.

24. The method according to claim 22 or 23,

wherein the reaction of acetic anhydride with at least one carboxylic acid of the formula (VII) is carried out according to the reaction equation

And/or

Wherein the reaction of acetic anhydride with the at least one carboxylic acid of the formula (VII) can 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 ℃; and/or

Wherein the reaction of acetic anhydride with the at least one carboxylic acid of formula (VII) 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, more in particular at about 1 bar.

25. The method of any one of claims 22 or 23,

wherein a symmetrical carboxylic anhydride of the formula (V) is produced and/or whereinThe radical R in the formula (V)¹⁵And R¹⁶Identical and represents an alkyl group having two or more carbon atoms; or

Wherein an asymmetric carboxylic anhydride of the formula (V) and/or wherein in the formula (V) the radical R is produced¹⁵And R¹⁶Different from each other, preferably wherein in formula (V) the radical R¹⁵And R¹⁶Each represents an alkyl group having two or more carbon atoms.

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

wherein, in the general formula (II), the group R⁵(iii) anhydrides of the formula (IIa) in which hydrogen is present

[CH₃-CH(OR⁴)-CH₂-C(O)]₂O (IIa)

Wherein in the general formula (IIa) the radical R⁴Have the meaning as defined above in respect of the above,

used instead of the free acid.

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

wherein, as reaction product, one or more lipids are obtained comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and corresponding to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Has the meaning defined hereinbefore, especially wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀-alkanesradical-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

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

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

linear (straight-chain) or branched, saturated or mono-or polyunsaturated CH₃-CH(OR⁴)-CH₂A radical of the type-C (O) -in which the radical R⁴Has the meaning defined hereinbefore, especially wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

29. The method according to claim 27 or 28,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Has the meaning defined hereinbefore, especially wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

30. The method of any one of claims 27 or 28,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

31. The method of any one of claims 27 to 29,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

32. The method according to claim 27 or 28,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

33. The method of any one of claims 27, 28 or 32,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

34. The method of any one of claims 27, 28 or 32,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

35. The method of any one of claims 27, 28 or 32,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C (O) -and the radical R⁶、R⁷And R⁸One represents a group C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -, and the radical R⁶、R⁷And R⁸One represents a group C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -.

36. A reaction product obtainable by the process according to any one of the preceding claims.

37. A reaction product, in particular a (chemical) product or a product mixture, in particular a reaction product according to claim 36,

wherein the reaction product comprises structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid corresponding to the lipid of formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

38. The reaction product of claim 36 or 37,

wherein the reaction product comprises one or more structural units comprising glycerol esters based on 3-hydroxybutanoic acid and/or 3-alkoxybutanoic acid and corresponds to a lipid of the general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

linear (straight-chain) or branched, saturated or mono-or polyunsaturated CH₃-CH(OR⁴)-CH₂A radical of the type-C (O) -in which the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

39. The reaction product of any one of claims 36 to 38,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

however, provided thatTwo radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

40. The reaction product of any one of claims 36 to 39,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

41. The reaction product of any one of claims 36 to 39,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

Radical ofGroup C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

42. The reaction product of any one of claims 36 to 38,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

43. The reaction product of any one of claims 36 to 38 or 42,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

44. The reaction product of any one of claims 36 to 38 or 42,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

45. The reaction product of any one of claims 36 to 38 or 42,

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

46. The reaction product of any of the preceding claims,

wherein the reaction product of formula (III) comprises at least two different compounds of formula (III) and/or wherein the reaction product comprises a mixture of at least two different compounds of formula (III).

47. The reaction product of any of the preceding claims,

wherein the reaction product of formula (III) comprises at least three different compounds of formula (III) and/or wherein the reaction product comprises a mixture of at least three different compounds of formula (III).

48. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

49. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to claim 48,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

linear (straight-chain) or branched, saturated or mono-or polyunsaturated CH₃-CH(OR⁴)-CH₂A radical of the type-C (O) -in which the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

50. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to claim 48 or 49,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

51. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to any one of claims 48 to 50,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein at the same timeIn the formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

52. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to any one of claims 48 to 50,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a groupCH₃-CH(OR⁴)-CH₂-C(O)-。

53. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to claim 48 or 49,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

54. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to any one of claims 48, 49 or 53,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

55. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to any one of claims 48, 49 or 53,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸Are the same or different and each independently represents

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

56. A lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate, particularly according to any one of claims 48, 49 or 53,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radicals R are identical or different⁶、R⁷And R⁸Each independently represents

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

57. A mixture of lipids comprising at least two different structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid of general formula (III) as described above.

58. A mixture of lipids comprising at least three different building blocks of general formula (III) as described above comprising glycerol esters based on 3-hydroxybutanoic acid and/or 3-alkoxybutanoic acid.

59. A pharmaceutical composition, in particular a drug or medicament, comprising the reaction product according to any one of claims 36 to 47 and/or at least one lipid according to any one of claims 48 to 56 comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and/or a mixture according to any one of claims 57 or 58.

60. The use of a pharmaceutical composition according to claim 59 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 disorder 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, 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, cancer such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and arthritic uremia, 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.

61. Use of the reaction product according to any one of claims 36 to 47 and/or at least one lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to any one of claims 48-56 and/or a mixture according to any one of claims 57 or 58 for the prophylactic and/or therapeutic treatment or for the prophylactic and/or therapeutic treatment of diseases of the human or animal body, in particular diseases associated with disorders of energy metabolism, in particular 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, lipid metabolism diseases such as defects in glucose transport (defects in GLUT 1), VL-FAOD and mitochondrial diseases such as defects in mitochondrial thiolase, huntington's disease, cancers such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis and arthritic uremia, gastrointestinal diseases such as chronic inflammatory bowel disease, particularly ulcerative colitis and crohn's disease, lysosomal storage diseases such as sphingolipid diseases, particularly niemann-pick disease, the effects or side effects of diabetes and chemotherapy.

62. Use of the reaction product according to any one of claims 36 to 47 and/or at least one lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to any one of claims 48-56 and/or a mixture according to any one of claims 57 or 58 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 a disease associated with a disturbance 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, lipid 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 arthritic uremia, 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.

63. Use of the reaction product according to any one of claims 36 to 47 and/or at least one lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to any one of claims 48-56 and/or a mixture according to any one of claims 57 or 58 for the prophylactic and/or therapeutic treatment or for the manufacture of a medicament for the prophylactic and/or therapeutic treatment or for the use in catabolic states such as hunger, diet or low carbohydrate nutrition.

64. A foodstuff and/or foodstuff comprising the reaction product according to any one of claims 36 to 47 and/or at least one lipid according to any one of claims 48 to 56 comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and/or a mixture according to any one of claims 57 or 58.

65. Food and/or foodstuff according to claim 64, 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 snack, an appetite suppressant or a strength and/or endurance exercise supplement.

66. Use of the reaction product according to any one of claims 36 to 47 and/or at least one lipid comprising structural units based on glycerol esters of 3-hydroxybutanoic acid and/or 3-alkoxybutanoic acid according to any one of claims 48 to 56 and/or of the mixture according to any one of claims 57 or 58 in food and/or foodstuff.

67. The use according to claim 66, 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 ketone bodies and related metabolism and treatment of related diseases.

In particular, the present invention relates to a process for producing lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate and to the reaction products (i.e. lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate) obtained thereby or prepared thereby and to their use, in particular in pharmaceutical compositions, such as medicaments or medicaments, or in food and/or foodstuff, and to their further applications or uses.

Furthermore, the present invention relates to pharmaceutical compositions, in particular medicaments or medicaments, comprising the reaction products obtained or produced according to the process of the invention (i.e. lipids comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid), as well as their uses or uses.

Finally, the present invention relates to foods and/or foodstuffs, in particular food supplements, functional foods, novel foods, food additives, food supplements, dietary foods, energy snacks, appetite suppressants and strength and/or endurance exercise supplements, comprising the reaction products (i.e. lipids comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid) obtained or produced according to the process of the present invention, as well as their use or use.

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, especially the human Central Nervous System (CNS) and the heart require a permanent energy supply.

Physiological alternatives to glucose, which are mainly used in the central nervous system, are the so-called ketone bodies (synonymously also called ketone bodies).

The term ketone bodies refers specifically to the collective name of three compounds that are formed primarily in catabolic states (e.g., starvation, reduced or low carbohydrate diet) and may lead to ketosis. The term ketone body specifically includes the three compounds acetoacetate (synonymously also referred to as acetoacetate) and acetone as well as 3-hydroxybutyrate (hereinafter synonymously also referred to as beta-hydroxybutyrate or BHB or 3-BHB) or salts thereof (i.e., 3-hydroxybutyrate or beta-hydroxybutyrate), the latter being the most important of the three compounds. The 3-hydroxybutyric acid or its salt is physiologically present in the form of the (R) -enantiomer, i.e., as (R) -3-hydroxybutyric acid (synonymously also referred to as (3R) -3-hydroxybutyric acid to emphasize the chiral center at the 3-position) or its salt.

During fasting or starvation, these ketone bodies are also provided in physiologically large quantities by lipids stored in the body through lipolysis and almost completely replace the energy source glucose.

Ketone bodies are formed in the liver from acetyl-CoA (═ acetyl-CoA), which results from β -oxidation; they represent 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 to acetyl-coa. Especially in starvation, ketone bodies make a considerable contribution to energy production. For example, over time, the brain can only sustain life by ingesting one third of daily glucose.

Physiologically, ketone bodies are synthesized from two molecules of activated acetic acid in the form of acetyl-CoA, a normal intermediate of fatty acid degradation, which is expanded to intermediate 3-hydroxy-3 methyl-glutaryl-CoA (HMG-CoA) using a further acetyl-CoA unit and the enzyme HMG-CoA-synthase, wherein finally the HMG-CoA-lyase cleaves acetoacetic acid. These three steps occur only in the mitochondria of the liver (the lynen cycle), where the 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, whereas 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 severe ketosis, ketoacidosis (e.g., in 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, 3-hydroxybutyrate is not known to humans, or only very small amounts of 3-hydroxybutyrate are known to humans, because plants do not produce 3-hydroxybutyrate, whereas 3-hydroxybutyrate in animals only occurs in lean animals which die from ketosis, and thus 3-hydroxybutyrate causes nausea when administered orally. The free acid form of 3-hydroxybutyric acid and its salts also tastes bitter, causing severe vomiting and nausea.

In addition, patients, particularly newborns and adults, cannot tolerate large amounts of the salt of 3-hydroxybutyrate for a long period of time because these compounds may have kidney-damaging effects.

Furthermore, 3-hydroxybutyrate and its salts have a very short plasma half-life, even if taken as a few grams, ketosis lasts only about three to four hours, 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 the treatment of 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) aimed at deriving 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 drug-pharmacological target molecule, which, according to the prior art, is in principle useful for the treatment of various diseases, but cannot be used due to its 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, by way of example only, and in no way by way of limitation, potential therapeutic 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 easy to obtain such compounds.

Disclosure of Invention

The problem underlying the present invention is therefore to provide an efficient method for the production of physiologically suitable or physiologically compatible precursors and/or metabolites of 3-hydroxybutyrate (i.e. synonymously also referred to as 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, especially on a large scale and without large amounts of toxic by-products.

In a completely surprising manner, the applicant has now found that lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate represent effective and physiologically effective or physiologically compatible precursors and/or metabolites of the ketone body 3-hydroxybutyrate or salts thereof, and has been able to find or develop herein 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 process for producing a lipid comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid 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 obtained according to the process of the present invention of the independent claim (claim 36) or a lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to the respective claims (claims 48 to 56), or a mixture of at least two lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to the respective claims (claims 57 and 58); in particular a mixture of at least three lipids; furthermore, particularly specific and/or advantageous embodiments of this aspect of the invention are the subject matter of the relevant dependent claims.

Also, according to a third aspect of the invention, the invention relates to a pharmaceutical composition, in particular a medicament or medicament, according to the respective independent claim (claim 59); 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 use of the reaction product according to the invention or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate or of a mixture of at least two, in particular at least three, different lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to the independent claims (claim 61) for the prophylaxis and/or therapeutic treatment or for the prophylaxis and/or therapeutic treatment of diseases 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 of the present invention or the lipid of the present invention comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate or the mixture of at least two, in particular at least three, different lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to the related independent claims (claim 62) 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.

Furthermore, according to a sixth aspect of the present invention, the present invention relates to the use of the reaction product of the present invention or the lipid of the present invention comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate or the mixture of at least two, in particular at least three, different lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate according to the related independent claim (claim 63).

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 64); 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 reaction product according to the invention or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyrate/3-alkoxybutyrate or the mixture of at least two, in particular at least three, different lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate/3-alkoxybutyrate according to the related independent claim (claim 63) in foods and/or foodstuffs; 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 to be regarded as 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 to be regarded as broadly disclosed with respect to all resulting combination possibilities.

With regard to all relative or percent 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 such that they always add up to 100% or 100% by weight, respectively, including all components or ingredients, in particular as 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 described this, the invention will be described in more detail below:

thus, according to a first aspect of the invention, the subject of the invention is a process for producing lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid,

wherein at least one glyceride of the general formula (I)

R¹O-CH₂-CH(OR²)-CH₂-OR³ (I)

Wherein in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

The presence of hydrogen in the gas phase,

a radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R¹、R²And R³At least one, preferably at least two, of which do not represent hydrogen, is reacted with at least one 3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivative of the general formula (II)

CH₃-CH(OR⁴)-CH₂-C(O)OR⁵ (II)

Wherein in the general formula (II)

The radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

the radical R⁵Represents hydrogen or C₁-C₄Alkyl, especially C₁-C₄Alkyl, preferably methyl or ethyl, more preferably ethyl,

thus, as reaction product, one or more lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid of general formula (III) are obtained

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Having the meaning as defined above, and which,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

As mentioned above, the applicant has very surprisingly found that the lipids thus produced comprising structural units based on glycerides of 3-hydroxybutyrate and/or 3-alkoxybutyrate are effective, since physiologically compatible precursors and/or metabolites of free 3-hydroxybutyrate or salts thereof can also be used in large quantities in pharmaceutical or clinical applications, since they are physiologically compatible.

The above-mentioned lipids comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, obtained for the first time in an efficient manner by the production process according to the present invention, represent a physiologically and pharmacologically relevant alternative to free 3-hydroxybutyric acid or salts thereof.

The production of such compounds by conventional organic synthesis is complex and expensive, since 3-hydroxybutyric acid has an increased tendency to polymerize and other undesired side reactions occur, such as dehydration, decomposition, etc. Within the scope of the present invention, for the first time an efficient production process is provided by which lipids comprising building blocks based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid can be produced without undesired side reactions, in particular in one step.

The method according to the invention therefore makes it possible for the first time to provide nontoxic lipids comprising building blocks based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid from known, commercially available and in particular physiologically harmless components or educts (starting compounds). The produced lipid comprising a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric 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 lipid comprising a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid further comprises an acceptable taste to ensure compatibility even when orally administered in a large amount over a long period of time (e.g., 50g or more per day).

Similarly, the production method according to the present invention can provide a lipid containing a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, which is free of 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. the (R) -enantiomer, to be enriched, in particular catalyzed by enzymes, so that it does not burden the renal system of the patient (i.e. 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 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 such 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 in the absence of a solvent and/or in the absence of 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 the solvent in an expensive and energy-consuming manner after carrying out the process or reaction. Furthermore, no toxic by-products are formed.

With regard to the starting compounds or educts of the general formula (I), the following should be mentioned:

according to a particular embodiment of the process according to the invention, it may be provided that, in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

The presence of hydrogen in the gas phase,

provided, however, that the group R¹、R²And R³At least one, preferably at least two of (a) do not represent hydrogen.

According to a further particular embodiment of the process according to the invention, it may be provided that, in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

Finally, according to a further particular embodiment of the process according to the invention, it may be provided that, in the general formula (I), the radical R¹、R²And R³The same or different, each independently represent

provided, however, that the group R¹、R²And R³At least one of them represents a linear (linear) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -, with the proviso that the radical R¹、R²And R³At least one of them represents a linear (linear) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

In particular, it can be provided that, in the formula (I), the radical R¹、R²And R³Identical or different, each independently of the others, represents a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁alkyl-C (O) -, in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -.

Furthermore, it can be provided that, in the general formula (I), the radical R¹、R²And R³Identical or different, each independently of the others, represents a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

With regard to the starting compounds or educts of the general formula (II), the following should be mentioned:

according to a particular embodiment of the process of the invention, provision may be made for

the radical R⁵Represents C₁-C₄-an alkyl group,in particular C₁-C₄-alkyl, preferably methyl or ethyl, more preferably ethyl.

According to another particular embodiment of the process according to the invention, provision may be made for

the radical R⁵Represents an ethyl group.

According to a further particular embodiment of the invention, it may be provided that, in the general formula (II), the radical R⁴Represents hydrogen and the radical R⁵Represents an ethyl group.

In particular, as 3-hydroxy-and/or 3-alkoxybutanoic acid derivatives of the general formula (II), the formula CH₃-CH(OH)-CH₂-C(O)OC₂H₅The ethyl 3-hydroxybutyrate (ethyl 3-hydroxybutyrate) can be used.

In principle, the 3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivatives of formula (II) may be used in racemic form or in the form of the (R) enantiomer. (R) -configuration is based in particular on the carbon atom in position 3 OR (R) -configuration is based on the carrying of OR⁴Carbon atoms of the group.

In particular, in the process of the invention, the reaction is carried out in the absence of a solvent and/or in the absence of any solvent. This means that the reaction proceeds 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.

In particular, according to the invention, it is provided that 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 particular the catalyst is recycled after the reaction.

According to a particular embodiment of the invention, the reaction may be carried out in the presence of an enzyme as catalyst.

The enzyme may in particular be selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof.

The enzymes may in particular be derived from Candida antarctica (Candida antarctica), Mucor miehei (Rhizomucor miehei), Thermomyces lanuginosus (Thermomyces lanuginosus), Candida rugosa (Candida rugosa), Aspergillus oryzae (Aspergillus oryzae), Pseudomonas cepacia (Pseudomonas cepacia), Pseudomonas fluorescens (Pseudomonas fluorescens), Rhizopus antarctica (Rhizopus delr) and Pseudomonas sp, and combinations thereof, preferably from Candida, Mucor miehei (Rhizomucor miehei) and Thermomyces lanuginosus.

In particular, the enzyme may 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, the enzyme may be recycled after the reaction.

If the reaction is carried out in the presence of an enzyme as catalyst, the reaction carried out in the presence of an enzyme as catalyst is in particular 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 ℃, even more preferably in the range from 50 ℃ to 70 ℃.

In particular, the enzymes are used in amounts starting from the total amount of compounds (I) and (II) 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.

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 about 1 bar.

According to another particular embodiment of the process of the invention, the reaction can be carried out in the presence of an acidic or basic catalyst containing a metal and/or a metal base.

In particular, the catalyst may be chosen in particular from (i) basic catalysts, in particular alkali metal or alkaline earth metal hydroxides and alkali metal or alkaline earth metal alcoholates, such as NaOH, KOH, LiOH, Ca (OH)₂NaOMe, KOMe and sodium tert-butoxide, (ii) acidic catalysts, especially inorganic acids, and organic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, nitric acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and carboxylic acids, (iii) lewis acids, especially lewis acids based on titanium, tin, zinc and aluminum compounds, such as tetrabutyl titanate, stannic acid, zinc acetate, aluminum trichloride and triisopropylaluminum (aluminum tri-isoproyl), and (iv) heterogeneous catalysts, especially based on mineral silicates, germanates, carbonates and aluminas, such as zeolites, montmorillonites, mordenite, hydrotalcite and alumina, and combinations thereof.

In particular, alkali metal or alkaline earth metal alcoholates can be used as catalysts.

In particular, it is preferable that the catalyst is recycled after the reaction.

According to the invention, the reaction can be carried out in particular in the presence of a metal-and/or metal-based acidic or basic catalyst 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 ℃, even more preferably in the range from 100 ℃ to 120 ℃.

The catalyst may in particular be used in an amount in the range from 0.01 to 30 wt.%, in particular in the range from 0.05 to 15 wt.%, preferably in the range from 0.1 to 15 wt.%, preferably in the range from 0.2 to 10 wt.%, based on the total amount of starting compounds (I) and (II).

The reaction may be carried out in the presence of a metal-containing and/or metal-based acidic or basic catalyst at a pressure in the range of 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.

For the production of the starting compounds or educts, the following should be mentioned:

in the general formula (I), the radical R¹、R²And R³At least one of which represents a group C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁In the case of alkyl-C (O) -and the radical R¹、R²And R³At least one of which represents a group C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-c (o) -, the glycerides of formula (I) are or can be obtained by suitable transesterification.

According to a particular embodiment of the process of the invention, the transesterification may be carried out by reacting under transesterification conditions at least one compound of the formula (Ia)

R⁹O-CH₂-CH(OR¹⁰)-CH₂-OR¹¹ (Ia)

Wherein in the general formula (Ia), the radical R⁹、R¹⁰And R¹¹The same or different, each independently represent

The presence of hydrogen in the gas phase,

a radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that there are at least two and preferably groups R⁹、R¹⁰And R¹¹And does not represent hydrogen, and is not,

with at least one compound of the formula (Ib)

R¹²O-CH₂-CH(OR¹³)-CH₂-OR¹⁴ (Ib)

Wherein in the general formula (Ib) the radical R¹²、R¹³And R¹⁴The same or differentEach independently represents

The presence of hydrogen in the gas phase,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that there are at least two and preferably groups R¹²、R¹³And R¹⁴Not representing hydrogen, or (vice versa)

At least one compound of formula (Ib) as defined above is reacted with at least one compound of formula (Ia) as defined above under transesterification conditions.

In the general formula (Ia), the radical R⁹、R¹⁰And R¹¹Identical or different, each independently of the others may represent in particular a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁-C₁₁Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₂-C₁₁-alkyl-C (O) -.

Furthermore, in the general formula (Ib), the radical R¹²、R¹³And R¹⁴Identical or different, each independently of the others may represent in particular a linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -.

In particular, provision may be made according to the invention for the radical R in the formula (Ia)⁹、R¹⁰And R¹¹In the case where one represents hydrogen, the compounds of the general formula (Ia) are obtainable and/or obtained by partial hydrolysis, in particular by partial (selective) enzymatically catalyzed hydrolysis, of the corresponding starting triglyceride of the general formula (Ia) in which the radical R⁹、R¹⁰And R¹¹None represent hydrogen and/or wherein the group R⁹、R¹⁰And R¹¹Identical or different, each independently represent a group C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -.

Furthermore, according to the invention, it can be provided in particular that in the general formula (Ib) the radical R¹²、R¹³And R¹⁴In the case where one represents hydrogen, it is possible to obtain compounds of the formula (Ib) in which the radical R is present and/or by partial hydrolysis, in particular partial (selective) enzymatic catalysis of the corresponding starting triglyceride of the formula (Ib)¹²、R¹³And R¹⁴None represent hydrogen and/or wherein the group R¹²、R¹³And R¹⁴Identical or different, each independently represent a group C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -.

According to a particular embodiment of the process of the invention, it is intended that the transesterification is carried out enzymatically.

According to this particular embodiment of the process of the invention, the transesterification is carried out according to this embodiment in the presence of an enzyme as catalyst, which may be selected from the group consisting of synthetases (ligases), catalases, esterases, lipases and combinations thereof. In particular, the enzyme may be derived from Candida antarctica, Mucor miehei (Rhizomucor miehei), Thermomyces lanuginosus, Candida rugosa, Aspergillus oryzae, Pseudomonas cepacia, Pseudomonas fluorescens, Rhizopus delleri, and Pseudomonas, and combinations thereof, preferably from Candida antarctica, Mucor miehei (Rhizomucor miehei), and Thermomyces lanuginosus. In particular, the enzyme may 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 support based on poly (meth) acrylic resins. Preferably, the enzyme may be recycled after transesterification.

In particular, the transesterification may be carried out in the presence of an enzyme as catalyst 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 ℃, even more preferably in the range of from 50 ℃ to 70 ℃.

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 (Ib).

The transesterification may be carried out in the presence of an enzyme as catalyst 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 a particular embodiment of the process according to the invention, it may be provided that, in the general formula (II), the radical R⁴Is a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁The 3-hydroxybutyric acid and/or 3-alkoxybutyric acid derivatives of formula (II) may be obtained or obtained by reacting compounds of formula (IV)

CH₃-CH(OH)-CH₂-C(O)OR⁵ (IV)

with at least one carboxylic anhydride of the general formula (V):

R¹⁵-C(O)-O-C(O)-R¹⁶ (V)

wherein in the general formula (V), the group R¹⁵And R¹⁶Identical or different, each independently represent a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

at R⁵Optionally followed by hydrolysis in the case of hydrogen.

In particular, the reaction of the at least one compound of the formula (IV) with the at least one carboxylic anhydride of the formula (V) can 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 ℃.

Furthermore, the reaction of the at least one compound of the formula (IV) with the at least one carboxylic anhydride of the formula (V) can be carried out 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, very particularly at about 1 bar.

In particular, during the reaction of at least one compound of the formula (IV) with at least one carboxylic anhydride of the formula (V), a compound of the formula (VI)

R¹⁷-C(O)-OH (VI)

Are formed simultaneously, wherein the radicals R¹⁷Represents a group R each having the meaning defined above¹⁵Or R¹⁶. In particular, the compounds of the formula (VI) can be removed during or after the reaction has taken place, in particular after the reaction has taken place, preferably by distillation.

According to a particular embodiment, provision may be made for the radical R in the formula (V)¹⁵And R¹⁶In the case of being different from each other, and/or the radical R in the formula (V)¹⁵，R¹⁶Each representing an alkyl group having more than two carbon atoms, the carboxylic anhydride of formula (V) being obtainable and/or obtained by reaction of acetic anhydride (acetic anhydride) with at least one carboxylic acid of formula (VII)

R¹⁸-C(O)-OH (VII)

In particular, the reaction of acetic anhydride with at least one carboxylic acid of the formula (VII) is carried out according to the reaction equation

The reaction of acetic anhydride with the at least one carboxylic acid of the formula (VII) can 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 of acetic anhydride with the at least one carboxylic acid of the formula (VII) 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, more in particular at about 1 bar.

According to this synthesis, it is possible in particular to prepare symmetrical carboxylic anhydrides of the formula (V). In particular, in the formula (V), the radical R¹⁵And R¹⁶Identical and represents an alkyl group having two or more carbon atoms.

However, according to an alternative embodiment, it is also possible to prepare asymmetric carboxylic anhydrides of the general formula (V) according to this synthesis. In particular, in the formula (V), the radical R¹⁵And R¹⁶May be different from each other. Preferably, in formula (V), the group R¹⁵And R¹⁶Each represents an alkyl group having two or more carbon atoms.

In the context of the production process according to the invention, the radical R in the formula (II)⁵(iii) anhydrides of the formula (IIa) in which hydrogen is present

[CH₃-CH(OR⁴)-CH₂-C(O)]₂O (IIa)

Wherein in the general formula (IIa) the radical R⁴Have the meaning as defined above in respect of the above,

can be used instead of the free acid.

In the context of the production process of the invention, as reaction product, one or more lipids are obtained which comprise structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and which correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

In particular, in the context of the production process of the invention, as reaction product, one or more lipids are obtained which comprise structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and which correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to one embodiment of the production process of the present invention, as a reaction product, one or more lipids are obtained which comprise structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and which correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁-alkyl-C (O) -, COther is C₂-C₁₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to another particular embodiment of the production process according to the invention, as reaction product one or more lipids are obtained comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and corresponding to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to another embodiment of the production process of the present invention, as the reaction product, one or more lipids are obtained which comprise structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and which correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to yet another particular embodiment of the production process according to the invention, as reaction product one or more lipids are obtained comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and corresponding to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁-alkyl-C (O) -,preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Furthermore, according to another particular embodiment of the production process of the present invention, as reaction product, one or more lipids are obtained comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and corresponding to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Finally, according to another particular embodiment of the production process according to the invention, as reaction product one or more lipids are obtained comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid and corresponding to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁-alkanesradical-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

As mentioned above, the process according to the invention is generally carried out in the absence of a solvent and/or in the absence of any solvent (i.e. 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.

The process of the present invention is illustrated by way of example only and not by way of limitation by the following general reaction scheme. In this scheme, the group R¹' represents a group C₁₂-C₂₉-alkyl, radical R²' represents a group C₁-C₁₁-alkyl, radical R³' represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁-alkyl-C(O) -, preferably C₃-C₂₁-alkyl-C (O) -. Radical R²' -MCT-oil means having a group R²' the triglyceride of (a). Radical R¹' -MCT-oil means having a group R¹' the triglyceride of (a). 3-acetoxy-BHB anhydride is the anhydride of 3-acetoxybutyric acid. 3-R³' -BHB-EE is ethyl 3-acetoxybutyrate. The abbreviation "cat" stands for a catalyst (e.g. an enzymatic or chemical catalyst, such as an alcoholate or the like). As shown in the following reaction scheme, different triglycerides of 3-BHB can be obtained with the process of the invention, which can be further randomized, in particular for example with medium and/or long chain triglycerides or fatty acids, in particular with so-called fish oils.

According to a second aspect of the invention, another subject is the reaction product obtainable according to the process of the invention or the reaction product of the invention (i.e. one or more lipids comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid) (see claims 36 to 47).

In particular, a subject of the invention according to this aspect of the invention is a lipid comprising structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, as defined in claims 48 to 56.

In particular, a subject of the invention according to this aspect of the invention is a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁-alkyl-C (O) -, COther is C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C (O) - (and preferably further provided that at all groups R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂In the case of-C (O) -at the radical R⁶、R⁷And R⁸In at least one of (A) is present in the group CH₃-CH(OR⁴)-CH₂The group R in (C) - (O)⁴Not representing hydrogen).

Furthermore, according to this aspect of the invention, the subject of the invention is a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

linear (straight chain)) Or branched, saturated or mono-or polyunsaturated C₁₂-C₂₉Groups of the type-alkyl-C (O) -in particular linear (straight-chain) or branched, saturated or mono-or polyunsaturated C₁₉-C₂₉-alkyl-C (O) -,

linear (straight-chain) or branched, saturated or mono-or polyunsaturated CH₃-CH(OR⁴)-CH₂A radical of the type-C (O) -in which the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁alkyl-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸At least one of which represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Also according to this aspect of the invention, another subject of the invention is a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

a radical CH₃-CH(OR⁴)-CH₂-C (O) -, wherein the radical R⁴Has the meaning defined hereinbefore, in particular wherein the radical R⁴Represents hydrogen or a group C₁-C₃₀alkyl-C (O) -, especially C₁-C₂₁-alkanesradical-C (O) -, preferably C₃-C₂₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to this aspect of the invention, another subject of the invention is a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Furthermore, according to this aspect of the invention, the subject of the invention is also a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that two radicals R⁶、R⁷And R⁸Represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Furthermore, according to this aspect of the invention, the invention relates to a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

According to this aspect of the invention, the invention also relates to a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

provided, however, that the group R⁶、R⁷And R⁸One represents a group CH₃-CH(OR⁴)-CH₂-C(O)-。

Finally, according to this aspect of the invention, another subject of the invention is a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, in particular as defined above,

wherein the lipids comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid correspond to general formula (III)

R⁶O-CH₂-CH(OR⁷)-CH₂-OR⁸ (III)

Wherein in the general formula (III), the radical R⁶、R⁷And R⁸The same or different, each independently represent

A radical C₁-C₁₁alkyl-C (O) -, especially C₂-C₁₁-alkyl-C (O) -,

a radical C₁₂-C₂₉alkyl-C (O) -, especially C₁₉-C₂₉-alkyl-C (O) -,

According to this aspect of the invention, another subject of the invention is a mixture of lipids comprising at least two different structural units based on glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid of general formula (III) as defined above.

In particular, another subject of the invention according to this aspect of the invention is a mixture of lipids comprising at least three different structural units of general formula (III) as defined above comprising glycerol esters based on 3-hydroxybutyric acid and/or 3-alkoxybutyric acid.

The reaction product obtainable respectively according to the process of the invention or the reaction product of the invention as defined above, and/or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable respectively according to the process of the invention or comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or the mixture obtainable respectively according to the process of the invention or the mixture of the invention as defined above, comprise various advantages and special features compared to the prior art:

as the applicants have surprisingly found that the reaction product obtainable, respectively, according to the process of the invention or the reaction product of the invention as defined above, and/or the lipid comprising, respectively, structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate obtainable, respectively, according to the production process of the invention or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate as defined above, and/or the mixture obtainable, respectively, according to the production process of the invention or the mixture of the invention as defined above, are particularly suitable as precursors or metabolites of 3-hydroxybutyrate or its salts, since, on the one hand, it is converted into 3-hydroxybutyrate or its salts physiologically, in particular in the gastrointestinal tract, and, on the other hand, it comprises at the same time a good physiological compatibility or tolerability, particularly with respect to non-toxic and acceptable organoleptic properties.

Furthermore, the reaction product obtainable, respectively, according to the process of the invention or the reaction product of the invention as defined above, and/or the lipid comprising, respectively, structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable, respectively, according to the production process of the invention or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or the mixture obtainable, respectively, according to the production process of the invention or the mixture of the invention as defined above, are readily available or can be obtained on a large scale on a synthetic basis, even on a commercial scale, and have the desired pharmaceutical or pharmacological quality.

Furthermore, the reaction product obtainable, respectively, according to the process of the invention or the reaction product of the invention as defined above, and/or the lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, respectively, obtainable according to the process of the invention or comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid, respectively, and/or the mixture obtainable, respectively, according to the process of the invention or the mixture of the invention as defined above, can, if desired, be provided in enantiomerically pure or enantiomerically enriched form.

The reaction product obtainable, respectively, according to the process of the invention or the reaction product of the invention as defined above, and/or the lipid of the invention comprising a structural unit based on a glyceride of 3-hydroxybutyrate and/or 3-alkoxybutyrate, respectively, obtainable according to the process of the invention or the lipid of the invention comprising a structural unit based on a glyceride of 3-hydroxybutyrate and/or 3-alkoxybutyrate, respectively, and/or the mixture obtainable, respectively, according to the process of the invention or the mixture of the invention as defined above, thus represent a pharmacological drug target effective in the context of ketone body therapy of the human or animal body.

The remaining aspects of the invention are explained in more detail below.

According to a third aspect of the present invention, another subject of the present invention is a pharmaceutical composition, in particular a drug or medicament, comprising the reaction product obtainable, respectively, according to the production process of the present invention or the reaction product of the present invention as defined above, and/or a lipid comprising the building blocks based on the glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable, respectively, according to the production process of the present invention or the lipid of the present invention comprising the building blocks based on the glycerides of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or a mixture obtainable, respectively, according to the production process of the present invention or the mixture of the present invention as defined above.

In particular, according to this aspect of the invention, the invention relates to a pharmaceutical composition for prophylactic and/or therapeutic treatment or for 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 arthritic uremia (artritis urica), gastrointestinal diseases such as chronic inflammatory bowel disease, in particular ulcerative colitis and crohn's disease, storage diseases such as sphingolipid diseases, 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 of the present invention is the reaction product obtainable, respectively, according to the production process of the present invention or the reaction product of the present invention as defined above, and/or a lipid comprising a structural unit based on a glyceride of 3-hydroxybutyrate and/or 3-alkoxybutyrate obtainable, respectively, according to the production process of the present invention or a lipid of the present invention comprising a structural unit based on a glyceride of 3-hydroxybutyrate and/or 3-alkoxybutyrate as defined above, and/or a mixture obtainable, respectively, according to the production process of the present invention or the mixture of the present invention as defined above, 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 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 (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 arthritic uremia, 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, respectively, according to the production process of the present invention or a reaction product of the present invention as defined above, and/or a lipid comprising a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable, respectively, according to the production process of the present invention or a lipid of the present invention comprising a structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or a mixture obtainable, respectively, according to the production process of the present invention or a mixture of the present invention as defined above, 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 with energy metabolism, in particular disorders associated with disturbances of 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, disorders of fat metabolism such as glucose transport deficiency (GLUT1 deficiency), VL-FAOD and mitochondrial disorders such as mitochondrial thiolase deficiency, Huntington's disease, cancers such as T-cell lymphoma, astrocytoma and glioblastoma, HIV, rheumatic disorders such as rheumatoid arthritis and arthritic uremia, gastrointestinal disorders 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 as defined above, respectively, and/or a lipid comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate obtainable according to the production process of the invention or a lipid of the invention comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate as defined above, respectively, and/or mixtures obtainable according to the production process of the invention or the inventive mixtures as defined above, respectively, 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 such as hunger, 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, respectively, according to the production process of the present invention or the reaction product of the present invention as defined above, and/or a lipid comprising the structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable, respectively, according to the production process of the present invention or the lipid of the present invention comprising the structural unit based on a glyceride of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or a mixture obtainable, respectively, according to the production process of the present invention or the mixture of the present invention as defined above.

According to a particular embodiment, the food and/or food 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, another subject of the present invention is the use of a reaction product obtainable, respectively, according to the production process of the present invention or a reaction product of the present invention as defined above, and/or of a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid obtainable, respectively, according to the production process of the present invention or of a lipid comprising structural units based on glycerol esters of 3-hydroxybutyric acid and/or 3-alkoxybutyric acid as defined above, and/or of a mixture obtainable, respectively, according to the production process of the present invention or of a mixture of the present invention as defined above, in 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):

production examples

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

Example 1:

production of mixed triglycerides with chains based on Long Chain Fatty Acids (LCFA), Medium Chain Fatty Acids (MCFA) and 3-hydroxybutyrate (BHB or 3-BHB), i.e.mixed Long Chain Fatty Acids (LCFA), Medium Chain Fatty Acids (MCFA) and 3-hydroxybutyrate (3-BHB) triglycerides

In a 2,000 ml multi-neck flask having a partial condenser (partial condenser) and a distillation bridge, 500 g of medium chain triglyceride (C) was added₈/C₁₀Fatty acids comprising triglycerides in a ratio of 60%/40%) and 900 g of long chain refined, bleached and deodorized fish oil (EPA/DHA content 20 to 50%, ratio 50:50) at 50 to 70 ℃ and vacuum: (<100 mbar) was stirred for 12 to 24 hours, using 14 g of immobilized enzyme (CALB). The enzyme was then filtered off. The reaction product was a randomized LCF/MCF triglyceride.

In a 2,000 ml multi-neck flask with a partial condenser (dephlegmator) and a distillation bridge, 1,000 g of the randomized LCF/MCF triglyceride prepared above were combined with 500 g of ethyl (R)/(S) -3-hydroxybutyrate (3-BHB ethyl ester) and 15g of an immobilized enzyme (CALB, e.g., an immobilized enzyme, e.g., CALB lipase on a polymer support, from Candida antarctica, e.g., from Sigma-Aldrich or Merck)435 or from Strem Chemicals, Inc435) At 50 to 70 ℃ and under vacuum (<500 mbar) was carried out for 24 to 36 hours. The enzyme was then filtered off.

The reaction product is LCF/MCF/3-BHB triglyceride or structured lipid.

Lysis experiments (lysis tests) of the reaction product in a gastric or intestinal medium (FaSSGF medium simulating the stomach or FaSSIF medium simulating the intestine), in each case in the presence or absence of pancreatin, demonstrated lysis to the free form of 3-BHB. These cleavage experiments demonstrate that lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate (in particular the reaction products obtained here) are effective precursors or metabolites of free 3-hydroxybutyrate or salts thereof, in particular with regard to their intended effect, and are also present in physiologically compatible forms.

Example 2:

production of mixed triglycerides with chains based on Long Chain Fatty Acids (LCFA) and 3-hydroxybutyrate (BHB or 3-BHB), i.e.mixed Long Chain Fatty Acids (LCFA) and 3-hydroxybutyrate (3-BHB) triglycerides

In a 1,000 ml multi-neck flask with a dephlegmator (partial condenser) and a distillation bridge, 500 g of long-chain, refined, bleached and deodorized fish oil (EPA/DHA content 20 to 50%, ratio 50:50) were transesterified with 200g of (r)/(S) -ethyl 3-hydroxybutyrate (ethyl 3-BHB) and 15g of immobilized enzyme (CALB) at 50 to 70 ℃ and under vacuum (<500 mbar) for 24 to 36 hours. The enzyme was then filtered off.

The reaction product is LCF/3-BHB triglyceride or structured lipid.

Example 3:

preparation of mixed medium-chain fatty acid (MCFA)/3-hydroxybutyric acid (3-BHB) triglycerides

In a 1,000 ml multi-necked flask with a partial condenser (partial condenser) and a distillation bridge, 500 g of medium chain triglycerides (containing C)₈/C₁₀Triglyceride of fatty acids in a ratio of 60%/40%) with 120 g of ethyl (R)/(S) -3-hydroxybutyrate (3-BHB ethyl ester) and 15g of immobilized enzyme (CALB) at 50 to 70 ℃ under vacuum: (<500 mbar) was carried out for 24 to 36 hours. The enzyme was then filtered off.

The reaction product is MCF/3-BHB triglyceride or structured lipid.

Example 4:

preparation of mixed Medium Chain Fatty Acid (MCFA) and 3-acetoxybutyric acid (Ac-BHB) triglycerides from partial glycerides and 3-acetoxybutyric anhydride

25 g of (R)/(S) -3-hydroxybutyric acid (3-BHB) was provided in 95 g of acetic acid in a 1,000 ml multi-necked flask with a partial condenser (partial condenser) and a distillation bridge. At 80 ℃ and N₂Under an atmosphere, 90g of acetic anhydride was added dropwise to the reaction mixture over 1 hour. The reaction mixture was stirred at 80 ℃ for a further 4 to 5 hours. 3 g of medium-chain mono/diglycerides (C)₈/C₁₀The proportion of fatty acids is 60%/40%; glyceride distribution: monoester 30 to 70%, diester 10 to 30%, triester 1 to 5%) was added to the reaction mixture at 80 ℃ and stirred for 4 to 5 hours. Under vacuum (<50 mbar) the resulting 3-acetoxybutyric acid or acetic acid is distilled off at from 100 to 120 ℃.

The reaction product was MCF/3-acetoxy-BHB triglyceride.

Example 5:

production of mixed Long Chain Fatty Acid (LCFA) and 3-acetoxybutyric acid (Ac-BHB) triglycerides from partial glycerides and 3-acetoxybutyric anhydride

500 g of long-chain, refined, bleached and deodorized fish oil (EPA/DHA content 20 to 50%, ratio 50:50) were charged in a 1,000 ml multi-neck flask with a partial condenser (partial condenser) and a distillation bridge with 250g of water and 0.4g of lipase at 40 ℃ under stirring and N₂And selectively cracking for 8 to 12 hours under the atmosphere. Most of the fatty acids<C₂₀Is separated. The phases were then separated and the organic phase was filtered. The organic phase is composed of free fatty acids (mainly)<C₂₀) And LCFA mono-, di-and triglycerides: (>C₂₀) And (4) forming. Distilling free fatty acids from the reaction mixture by short path distillation under vacuum at a temperature of 140 to 180 ℃ ((<C₂₀). LCFA is obtained (>C₂₀) A mixture of mono-, di-and triglycerides.

The reaction product was LCF/acetyl-BHB triglyceride (3-acetoxy-BHB triglyceride).

Example 6:

preparation of mixed Long Chain Fatty Acid (LCFA), Medium Chain Fatty Acid (MCFA) and 3-acetoxybutyric acid (Ac-BHB) triglycerides from partial glycerides and 3-acetoxybutyric anhydride

500 g of long-chain, refined, bleached and deodorized fish oil (EPA/DHA content 20 to 50%, ratio 50:50) were charged in a 1,000 ml multi-neck flask with a partial condenser (partial condenser) and a distillation bridge with 250g of water and 0.4g of lipase at 40 ℃ under stirring and N₂And selectively cracking for 8 to 12 hours under the atmosphere. Most of the fatty acids<C₂₀Is separated. The phases were then separated and the organic phase was filtered. The organic phase is composed of free fatty acids (mainly)<C₂₀) And LCFA (>C₂₀) And monoglycerides, diglycerides and triglycerides. Distilling free fatty acids from the reaction mixture by short path distillation under vacuum at a temperature of 140 to 180 ℃ ((<C₂₀). LCFA is obtained (>C₂₀) A mixture of mono-, di-and triglycerides.

25 g of (R)/(S) -3-hydroxybutyric acid (3-BHB) was provided in 95 g of acetic acid in a 1,000 ml multi-necked flask with a partial condenser (partial condenser) and a distillation bridge. At 80 ℃ and N₂Under an atmosphere, 90g of acetic anhydride was added dropwise to the reaction mixture over 1 hour. The reaction mixture was stirred at 80 ℃ for a further 4 to 5 hours. 30 g of LCFA prepared above (A)>C₂₀) And 7.5 grams of medium chain mono-, di-, and triglycerides (C)₈/C₁₀Fatty acid, the proportion is 60%/40%; glyceride distribution: monoester 30 to 70%, diester 10 to 30%, triester 1 to 5%) was added to the reaction mixture at 80 ℃ and stirred for 4 to 5 hours. Under vacuum (<50 mbar) and the resulting 3-acetoxybutyric acid is distilled off at from 100 to 120 ℃. The remaining reaction product is now immobilized with an immobilized enzyme (CALB) at 40 ℃ and N₂Atmosphere(s)Randomization was performed with stirring for 8 to 12 hours.

The reaction product was LCF/MCF/acetyl-BHB triglyceride (3-acetoxy-BHB triglyceride).

Example 7:

production of mixed Long Chain Fatty Acid (LCFA), Medium Chain Fatty Acid (MCFA) and 3-hydroxybutyrate (3-BHB) triglycerides from partial glycerides

500 g of long-chain, refined, bleached and deodorized fish oil (EPA/DHA content 20 to 50%, ratio 50:50) were charged in a 1,000 ml multi-neck flask with a partial condenser (partial condenser) and a distillation bridge with 250g of water and 0.4g of lipase at 40 ℃ under stirring and N₂And selectively cracking for 8 to 12 hours under the atmosphere. Most of the fatty acids<C₂₀Is separated. The phases were then separated and the organic phase was filtered. The organic phase is composed of free fatty acids (mainly)<C₂₀) And LCFA (>C₂₀) And monoglycerides, diglycerides and triglycerides. Distilling free fatty acids from the reaction mixture by short path distillation under vacuum at a temperature of 140 to 180 ℃ ((<C₂₀). LCFA is obtained (>C₂₀) A mixture of mono-, di-and triglycerides.

In a 250 ml multi-neck flask with partial condenser (partial condenser) and distillation bridge, 50g of LCFA (LCFA) (prepared as described above) were placed>C₂₀) Of a mixture of mono-, di-and triglycerides, 25 g of medium chain mono-, di-and diglycerides (C)₈/C₁₀The fatty acid proportion is 60%/40%; glyceride distribution: the monoester content is 30-70%Diester 10 to 30%, triglyceride 1 to 5%) and 35 g of ethyl (R)/(S) -3-hydroxybutyrate (3-BHB ethyl ester) at 50 to 70 ℃ under vacuum (C.), (3-BHB ethyl ester)<500 mbar) were transesterified with 0.85 g of immobilized enzyme (CALB).

The reaction product was LCF/MCF/3-BHB triglyceride.

Example 8:

preparation and subsequent reaction of 3-acetoxy ethyl butyrate (3-Ac-BHB ethyl ester)

In a 250 ml multi-necked flask having a partial condenser (partial condenser) and a distillation bridge, 50g of ethyl (R)/(S) -3-hydroxybutyrate (racemic 3-BHB ethyl ester) and 55 g of acetic anhydride were charged. The reaction mixture was stirred and refluxed at 100 ℃ for 10 hours to effect a reaction. The acetic acid and excess acetic anhydride were then distilled off under vacuum. Ethyl 3-acetoxybutyrate was obtained with a purity of 98%. Characterization was by Gas Chromatography (GC) and GC-MS analysis (gas chromatography coupled with mass spectrometry). The conversion results/time curves are summarized in the table below.

Further conversion and application experiments of ethyl 3-acetoxybutyrate (ethyl 3-Ac-BHB) are described below: furthermore, it can be shown that the ethyl 3-acetoxybutyrate thus obtained can be used as starting material in transesterification reactions using enzymes as catalysts (e.g.immobilized enzymes, such as CALB lipase on a polymer support, from Candida antarctica, e.g.from Sigma-Aldrich or Merck

435 or from Strem Chemicals, Inc435) Glycerides were formed (reaction at 50 to 70 ℃ C., 24 hours 1 wt% enzyme). Triacetin was used as a further starting material; since it already contains acetyl groups, no unwanted by-products are formed during any transesterification on the already acetylated OH groups of the 3-BHB ethyl ester. Only ethyl acetate is formed as a by-product and can be easily removed. A mixture of mono-, di-and triglycerides of 3-acetoxybutyric acid is formed. The product is an analogue or model substance of the product according to the invention.

Lysis experiments (lysis tests) of this mixture in gastric or intestinal medium (FaSSGF medium mimicking the stomach or FaSSIF medium mimicking the intestinal tract), in each case with or without pancreatin, demonstrated lysis to 3-BHB in free form (a cascade of lysis from triglycerides via diglycerides to monoglycerides and then to free 3-BHB). These cleavage experiments demonstrate that the glycerol ester of blocked 3-hydroxybutyric acid or a salt thereof is an effective precursor or metabolite of free hydroxybutyric acid or a salt thereof, in particular with regard to their intended effect, also in a physiologically compatible form.

Example 9:

further production examples: carboxylic anhydride Synthesis (educts)

According to the carboxylic anhydride production method, heptanoic acid (C) is first produced₇Acid), lauric acid (C)₁₂Acid) and oleic acid (C)₁₈Acids) carboxylic acid anhydrides.

To prepare heptanoic acid (C)₇Acid), 860 g of heptanoic acid was placed in a 2,000 ml multi-neck flask having a partial condenser (partial condenser) and a distillation bridge, and 445 g of acetic anhydride was added with stirring at 90 ℃. The reaction mixture was then stirred at 130 ℃ under reflux for 6 hours. Then distilling off the ethyl acetate under vacuumAcid and excess acetic anhydride. To obtain the heptanoic anhydride. Characterization was performed by GC and GCMS.

Lauric acid (C)₁₂Acid) and oleic acid (C)₁₈Acids) are produced in the same manner.

Subsequently-corresponding to the production of ethyl 3-acetoxybutyrate-the relevant carboxylic anhydride was reacted with ethyl 3-BHB to give ethyl 3-BHB which was capped at the 3-position with carboxylic anhydride. These can be used as educts in the synthesis.

Physiological application test: in vitro digestion test

Digestion experiments (cleavage or splitting experiments) of Compounds of the invention

It was shown by lysis experiments that the reaction products produced according to the invention or their mixtures (reaction products from the preceding examples 1 to 7) can be lysed in the human gastrointestinal tract. The reaction products from examples 1 to 7 obtained and purified as described above were subjected to cleavage experiments as described below.

For lysis experiments under similar body conditions, two media were studied:

FaSSGF, gastric mimic

FaSSIF, intestinal tract mimicking

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

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

All experiments showed that the desired free acid 3-BHB was produced. The conversion/time course of the hydrolysis of the compounds according to the invention, including the increase in the acid number over time, demonstrates the decomposition of the desired educt into the free acid (3-BHB). This was confirmed by appropriate analysis.

The cleavage experiments described previously demonstrated that lipids comprising structural units based on glycerol esters of 3-hydroxybutyrate and/or 3-alkoxybutyrate are effective precursors or metabolites of free hydroxybutyrate or salts thereof, particularly with respect to their intended effect, and are also present in physiologically compatible forms.

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Method for producing lipids comprising structural units based on glycerides of hydroxycarboxylic acids

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