The present invention relates to a synthesis of specific carotenoid butyrates as well as to new compounds and their use. Butyrate compounds are very useful compounds, either as such or as intermediates in organic synthesis.

Butyrates are seen as very useful and healthy compounds.

It is known that butyrates fuels colonocytes, and in return these cells help provide an oxygen- free environment in which beneficial gut microbes thrive. This keeps inflammation in check, gut cells healthy, and gut bacteria in a good state.

Higher butyrate levels have been shown to increase levels of glutathione, an antioxidant produced in the body’s cells which neutralises free radicals in the gut. This is good because free radicals are linked to inflammation and many diseases.

Butyrates stop some of the pro-inflammatory substances in the human body from working. The anti-inflammatory effect of butyrate reduces oxidative stress and controls the damage caused by free radicals.

Furthermore, research shows that butyrates enhance the secretion of gut hormones like glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). GLP-1 increases insulin production and reduces glucagon production in the pancreas. PYY increases the uptake of glucose in both muscles and fatty tissue.

Increased production of short-chain fatty acids, including butyrate in the colon, increases the release of these gut hormones, indicating potential benefits for managing blood sugar levels and preventing weight gain.

Furthermore, butyrates can be used as intermediates in organic synthesis to produce i.e. useful carotenoid compounds.

The main problem with the butyrates is the strong (fishy) odour. Such an odour is such that most persons are not able to swallow such a compound even in very low concentration.

Due to the importance of butyrates, the goal of the present invention was to provide a way to produce butyrate compounds having all advantages but not having the strong unpleasant odour in a good yield.

Surprisingly, it was found that specific new butyrate compounds as defined by the formula below can be obtained in good yields by a new and easy process. Therefore, the present invention relates to a process (P) for producing compounds of formula

(the * always shows where it is attached to the backbone) wherein

Rs is -0(C0)(CH ₂ ) ₂ CH ₃ , -OH or -H, and R ₄ is -0(C0)(CH ₂ ) ₂ CH ₃ , -OH or -H, and Ri is a moiety wherein

Rs is -0(C0)(CH ₂ ) ₂ CH3, -OH or -H, with the proviso that at least one of the substituent R ₃ , R ₄ and R ₅ is a -0(C0)(CH ₂ ) ₂ CH ₃ moiety, by reacting a compound of formula (G) wherein R ₃ is -OH or -H, and R ₄ is -OH or -H, and

Ri is a moiety wherein

Rs is -OH or -H, with the proviso that at least one of the substituents R ₃ , R ₄ and Rs is -OH, with a compound of formula (II) wherein X is a halogen (such as Cl, Br, or F) or a group -0(C0(CH2)2CH3, in the presence of at least one base.

Preferred compounds of formula (I) are those of formula (la), (lb) (lc), (Id) and (le) wherein the substituents R3, R4 and Rs have the same definition as defined above and wherein at least one of R3, R4 and Rs is a -0(C0)(CH2)2CH3 moiety. The OH group of the compounds of formula (G) are the transformed into the butyrate when carrying out the process according to the present invention.

Therefore, the present invention relates to a process (P1) for producing compounds of formula (la)

Rs is -0(C0)(CH ₂ )2CH _3, -OH or -H and Rs is -0(C0)(CH ₂ ) ₂ CH ₃ , -OH or -H, with the proviso that at least one of the substituent R ₃ and Rs is a -0(C0)(CH ₂ ) ₂ CH ₃ moiety, by reacting a compound of formula (I’a)

R ₃ is -OH or -H and Rs is -OH or -H, with the proviso that at least one of the substituents R ₃ , and Rs is -OH, with a compound of formula (II) wherein X is a halogen or a group -0(C0(CH2)2CH3, in the presence of at least one base.

Therefore, the present invention relates to a process (P2) for producing compounds of formula (lb)

R ₃ is -0(C0)(CH ₂ ) ₂ CH3, by reacting a compound of formula (I’b) with a compound of formula (II) wherein

X is a halogen or a group 0(C0(CH ₂ ) ₂ CH ₃ in the presence of at least one base.

Therefore, the present invention relates to a process (P3) for producing compounds of formula (lc) wherein

R ₄ is -0(C0)(CH ₂ ) ₂ CH3, -OH or -H and Rs is -0(C0)(CH ₂ )2CH ₃ , -OH or -H, with the proviso that at least one of the substituent R ₄ and Rs is a -0(C0)(CH ₂ ) ₂ CH3 moiety, by reacting a compound of formula (Go) wherein

R ₄ is -OH or -H and Rs is -OH or -H, with the proviso that at least one of the substituents R ₃ and Rs is -OH, with a compound of formula (II) wherein

X is a halogen or a group -0(C0(CH ₂ ) ₂ CH ₃ and in the presence of at least one base.

Therefore, the present invention relates to a process (P4) for producing compounds of formula (Id)

R ₃ is -0(C0)(CH ₂ ) ₂ CH ₃ , by reacting a compound of formula (I’d) with a compound of formula (II) wherein X is a halogen or a group -0(C0(CH ₂ ) ₂ CH ₃ and in the presence of at least one base.

Therefore, the present invention relates to a process (P5) for producing compounds of formula (le)

R ₄ is -0(C0)(CH ₂ )2CH ₃ , by reacting a compound of formula (I’e) with a compound of formula (II) wherein

X is a halogen or a group -0(C0(CH2)2CH3 in the presence of at least one base.

The process according to the present invention is carried out in the presence of at least one base. Usually and preferably the base is a nitrogen base. Suitable bases are pyrimidine, pyridine purine, methylimidazole or trialkyl amines, (e.g. triethyl amine, diisopropylethyl amine).

Therefore, the present invention relates to a process (P6), which is process (P), (P1), (P2), (P3), (P4) or (P5), wherein the at least one base is a nitrogen base. Therefore, the present invention relates to a process (P6’), which is process (P6), wherein the nitrogen base is chosen from the group consisting of pyrimidine, pyridine purine, methylimidazole or trialkyl amines, (e.g. triethyl amine, diisopropylethyl amine).

The base is added to the reaction mixture in a molar ratio of 1 :1 : to 3 :1 in view of the compound of formula (II).

Therefore, the present invention relates to a process (P7), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6) or (P6’), wherein the at least one base is used in a molar ratio of 1 :1 : to 3 :1 in view of the compound of formula (II).

The compound of formula (II) is used in excess in view of the compound of formula (G). It is clear that when two OH groups in compounds of formula (G) are to be acetylated the molar excess of the compound of formula (II) is more than 2.

The molar ratio of the compound of formula (II) to the compound of formula (I’) is 1 : 1 to 3:1 , when one OH group in the compound of formula (G) is to be acetylated.

The molar ratio of the compound of formula (II) to the compound of formula (I’) is 2:1 to 6:1 , when two OH groups in the compound of formula (I’) are to be acetylated.

Therefore, the present invention relates to a process (P8), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6), (P6’) or (P7), wherein the molar ratio of the compound of formula (II) to the compound of formula (G) is 1 :1 to 3:1 , when one OH group in the compound of formula (G) is to be acetylated.

Therefore, the present invention relates to a process (P8’), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6), (P6’) or (P7), wherein the molar ratio of the compound of formula (II) to the compound of formula (G) is 2:1 to 6:1 , when two OH groups in the compound of formula (G) are to be acetylated.

The process according to the present invention can be carried without any solvent or it can be carried out in at least one inert solvent.

When using a solvent the solvent is usually a polar aprotic or apolar aprotic solvent. Suitable solvents are dichloromethane or trichloromethane.

Therefore, the present invention relates to a process (P9), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6), (P6’), (P7), (P8) or (P8’), wherein the process is carried without any solvent.

Therefore, the present invention relates to a process (P10), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6), (P6’), (P7), (P8) or (P8’), wherein the process is carried in at least one solvent, wherein the solvent is a polar aprotic or apolar aprotic solvent.

Therefore, the present invention relates to a process ( P 10’ ) , which is process (P10), wherein the solvent is chosen from the group consisting of dichloromethane and trichloromethane.

The process according to the present invention is carried out at a temperature of 10°C to 50° C.

Therefore, the present invention relates to a process (P11), which is process (P), (P1), (P2), (P3), (P4), (P5), (P6), (P6’), (P7), (P8), (P8’), (P9), (P10) or (P10’), wherein the process is carried out at a temperature of 10°C to 50° C.

At the end of the reaction process the product (compound of formula (I)) is isolated using commonly known methods. Usually using filtration.

The product (compound of formula (I)) can the also be purified further.

The present invention also relates to new compounds. The new compounds are the ones of formulae (If) to (lo)

As stated above the compounds of formula (I) can be used as such or in any formulation in the field of food, feed, pharma and personal care applications.

The compounds of formula (I) can also be used as intermediates in organic synthesis.

Preferably the present invention relates to the use of the compounds of formula (la), (lb) (lc), (Id) and/or (le) in food, feed, pharma and personal care applications.

Preferably the present invention relates to the use of the compounds of formula (la), (lb) (lc), (Id) and/or (le) as intermediates in organic synthesis.

More preferably the present invention relates to the use of the compounds of formula

(le), (If) (Ig), (Ih), (li), (Ij), (Ik), (Im), (In) and/or (lo) in food, feed, pharma and personal care applications.

Preferably the present invention relates to the use of the compounds of formula (le),

(Lf) (Ig), (Ih), (li), (Ij), (Ik), (Im), (In) and/or (lo) as intermediates in organic synthesis.

The following examples illustrate the invention further without limiting it. All percentages and parts, which are given, are related to the weight and the temperatures are given in °C, and the pressures are absolute pressures when not otherwise stated. Examples

Example 1:

A solution of beta-cryptoxanthin (1 .705 g, 3.00 mmol) in dichloromethane (30 ml) was cooled to 17 °C with a cooling bath. To this suspension, pyridine (0.291 ml, 3.60 mmol) and butyryl chloride (0.378 ml, 3.60 mmol) were added drop wise within 4min, whereby the temperature increased to 20 °C. After 3h at room temperature only partial conversion was observed (TLC). Therefore, more pyridine (0.097 ml, 1.200 mmol) and butyryl chloride (0.126 ml, 1.200 mmol) were added drop wise and stirring was continued. After another 1 h 30min the reaction was complete and ethanol (20 ml) was added slowly to remove access of butyryl chloride. The product was crystallized from dichloromethane / ethanol (30 ml). The crystalline product was removed by filtration, washed with ethanol (2 x 5.0 ml) and dried overnight in vacuo (10 mbar). Beta-cryptoxanthin butyrate was obtained as purple crystals (1.72 g) in 92% yield.

Example 2

Under inert gas atmosphere, to a solution of adonirubin (0.254 g, 0.385 mmol) in dichloromethane (10 ml) was added pyridine (0.050 ml, 0.616 mmol) and butyryl chloride (0.065 ml, 0.616 mmol) drop wise within 2min, whereby the temperature increased to 23.5 °C. After 90min at room temperature only partial conversion was observed (TLC). Therefore, after 1.5h more pyridine (0.050 ml, 0.616 mmol) and butyryl chloride (0.068 ml, 0.616 mmol) were added drop wise and stirring was continued. After another 3h 45min the reaction solution was warmed to 35 °C for 30min. Then, ethanol (10 ml) was added slowly to remove access of butyryl chloride. The product was crystallized from dichloromethane / ethanol (10 ml). The crystalline product was removed by filtration (G3 sinter) and washed with ethanol (2 x 1.0 ml). Additional crystals were recovered from the mother liquor by filtration over a membrane filter. These crystals were also rinsed with ethanol (2 x 1.0 ml). The combined crystalline material was dried in high vacuo for 2h at 35 °C. Adonirubin butyrate was obtained as purple crystals (0.127 g) in 50% yield.

Example 3

Under inert gas atmosphere, to a solution of 3-hydroxyechinenone (0.45 g, 0.794 mmol) in dichloromethane (10 ml) was added pyridine (0.103 ml, 1.270 mmol) and butyryl chloride (0.133 ml, 1.270 mmol) drop wise 6min, whereby the temperature increased to 21 °C. After 60min at room temperature only partial conversion was observed (TLC). Therefore, subsequently more pyridine (0.077 ml, 0.953 mmol) and butyryl chloride (0.10 ml, 0.935 mmol) were added drop wise and stirring was continued. After another 3h 45min, the reaction mixture warmed to 35 °C for 30min. Then, ethanol (7 ml) was added slowly to remove access of butyryl chloride. The product was crystallized from dichloromethane / ethanol (10 ml). The crystalline product was removed by filtration (G3 sinter) and washed with ethanol (2 x 2.0 ml). The crystalline material was dried overnight at r.t. and 10mbar. 3-Hydroxyechinenone butyrate was obtained as purple crystals (0.127 g) in 54% yield.

Example 4

Under inert gas atmosphere, to a solution of 3’-hydroxyechinenone (0.45 g, 0.780 mmol) in dichloromethane (10 ml) was added pyridine (0.076 ml, 0.935 mmol) and butyryl chloride (0.098 ml, 0.935 mmol) drop wise within 6min, whereby the temperature increased to 21 °C.

After 90min at room temperature only partial conversion was observed (TLC). Therefore, after 1 h 45min more pyridine (0.025 ml, 0.312 mmol) and butyryl chloride (0.033 ml, 0.312 mmol) were added drop wise and stirring was continued. After another 1h 15min at r.t. the reaction was completed. Then, ethanol (7 ml) was added slowly to remove access of butyryl chloride. The solvents were removed under reduced pressure and the resulting oily residue was dried in high vacuum. 3’-Hydroxyechinenone butyrate was obtained as dark-red amorphous solid (0.43 g) as a mixture of three isomers in 87% yield (sum of isomers).