The present invention relates to new specific butyrate compounds to a new and improved synthesis of specific butyrates as well 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 butyrate compounds as defined by the formula below can be obtained in good yields and selectivities by a new and easy process. Therefore, the present invention relates to a process (P) for producing a compound of formula wherein

Ri and R ₂ are independently of each other a linear or branched Ci - C ₆ alkyl group;

-NH ₂ ; -NO ₂ ; -OH; -OR ₄ ; or -CN, wherein R ₄ is a linear or branched Ci - Ce alkyl group, (preferably a linear or branched Ci-C ₄ alkyl group) or a Cs-Cy-cycloalkyl, n and m are independently of each other an integer having a value of 0 or 1 and characterized in that in a first step (step (i)) a compound of formula (II) wherein

Ri, R ₂ , R ₄ , n and m have the same meanings as in formula (I) and

R ₃ is a linear or branched Ci - Cw alkyl group is reacted with NH ₃ , in the presence of a catalyst, and in a second step the reaction product of step (i) is reacted with a compound of formula (III) wherein X is Cl or-0(CO)CH ₂ CH ₂ CH ₃ (preferably X is -O(CO)CH ₂ CH ₂ CH ₃ ). The reaction product obtained in step (ii) is the compound of formula (I).

Preferred compounds of formula (I) are those wherein

Ri and R ₂ are independently of each other Ci - C ₂ alkyl group; -NH ₂ ; -NO ₂ ; -OH; or

-OCH3, and n and m are independently of each other an integer having a value of 0 or 1 .

Most preferred is the compound of formula (la)

To obtain the final reaction products (compounds of formula (I)) the following compounds of formula (II) are used:

Preferred are compounds of formula (II) wherein

R1 and R ₂ are independently of each other Ci - C ₂ alkyl group; -NH ₂ ; -NO ₂ ; -OH; or -OCH3, and n and m are independently of each other an integer having a value of 0 or 1 , and R ₃ is Ci-C ₆ alkyl.

Most preferred is the compound of formula (Ila) wherein

R ₃ is Ci - C ₄ alkyl group.

Therefore, the present invention relates to a process (P1), which is process (P), wherein compounds of formula (II) wherein

R1 and R ₂ are independently of each other Ci - C ₂ alkyl group; -NH ₂ ; -NO ₂ ; -OH; or -OCH3, and n and m are independently of each other an integer having a value of 0 or 1 , and

R3 is Ci-Ce alkyl, are used.

Therefore, the present invention relates to a process (P2), which is process (P), wherein the compounds of formula (Ila) wherein

R ₃ is Ci - C ₄ alkyl group, are used. In the following the two reaction steps are discussed and described in more detail.

Step (i)

As stated above in the first step (a compound of formula (II) wherein

Ri, R ₂ , n and m have the same meanings as in formula (I) and

R ₃ is a linear or branched Ci - Cw alkyl group is reacted with NH ₃ , in the presence of a catalyst,

Step (i) is usually under pressure. The pressure used (by the NH ₃ ) is usually between 2 to 50 bar.

Therefore, the present invention relates to a process (P3), which is process (P), (P1) or (P2), wherein step (i) the pressure is 2 to 50 bar.

The reaction temperature in the first reaction step is usually between 10 and 50°C.

Therefore, the present invention relates to a process (P4), which is process (P), (P1), (P2) or (P3), wherein step (i) the reaction temperature is between 10 and 50°C.

The catalyst used in step (i) is an ammonium salt.

Examples of ammonium salts of formula NH ₄ Y are those wherein Y is the anion of an inorganic acid such as a hydrogen halogenide, sulphuric acid and phosphoric acid or of a strong organic acid well-known in the art.

In case of two- or three-basic acids mono-, di and tri-basic ammonium salts can be used as well as mixed metal/ammonium salts, the metal being, e.g., iron(ll) or an alkali metal, preferably sodium or potassium. Examples of strong organic acids are carboxylic acids (mono-, di-, tri-, polybasic), such as, formic acid, acetic acid, trifluoro-acetic acid and citric acid.

A very suitable and preferred catalyst is NH ₄ CI. Therefore, the present invention relates to a process (P5), which is process (P), (P1), (P2), (P3) or (P4), wherein step (i) the catalyst is an ammonium salt of formula NH4Y, wherein Y is the anion of an inorganic acid such as a hydrogen halogenide, sulphuric acid and phosphoric acid or of a strong organic acid.

Therefore, the present invention relates to a process (P5’), which is process (P5), wherein step (i) the catalyst is NH ₄ CI.

The amount of catalyst in the reaction is not critical and can vary in a wide range. The amount of the catalyst is usually 0.5 - 20 mol-% (in regard to the compound of formula (II)), preferably 1 - 15 mol-% (in regard to the compound of formula (II)).

Therefore, the present invention relates to a process (P6), which is process (P), (P1), (P2), (P3), (P4), (P5) or (P5’), wherein step (i) the amount of the catalyst is 0.5 - 20 mol-% (in regard to the compound of formula (II)).

Therefore, the present invention relates to a process (P6’), which is process (P), (P1), (P2), (P3), (P4), (P5) or (P5’), wherein step (i) the amount of the catalyst is 1 - 15 mol-% (in regard to the compound of formula (II)).

NH ₃ , which is used as a gas, can is usually used in excess in view of the compound of formula (II).

Step (i) is usually carried for 1 - 30 h. Afterward the reaction product is usually washed and purified and the used in the following step (ii).

The reaction product of step (i) is the compound of formula (IV) wherein Ri, R2,R4, m and n have the same meaning as in formula (II). Step (ii)

In the second step the reaction product of step (i), which is the compound of formula (IV) is reacted with a compound of formula (III) wherein X is Cl or-0(CO)CH ₂ CH ₂ CH ₃ (preferably X is -O(CO)CH ₂ CH ₂ CH ₃ ).

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 or purine.

Therefore, the present invention relates to a process (P7), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6) or (P6’), wherein step (ii) is carried out in the presence of at least one base.

Therefore, the present invention relates to a process (P7’), which is process (P7), wherein the at least one base is a nitrogen base.

Therefore, the present invention relates to a process (P7”), which is process (P7) or (P7’), wherein the nitrogen base is chosen from the group consisting of pyrimidine, pyridine and purine.

The amount of the base in the reaction is not critical and can vary in a wide range.

The base (or the mixture of bases) is added usually in amount of 5 - 50 mol-% (in regard to the compound of formula (IV).

Therefore, the present invention relates to a process (P8), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’) or (P7”), wherein step (ii) the at least one base is added in amount of 5 - 50 mol-% (in regard to the compound of formula (IV)).

Usually the compound of formula (III) is used in excess (in view of the compound of formula (IV)).

Therefore, the present invention relates to a process (P9), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’), (P7”) or (P8), wherein step (ii) the compound of formula (III) is used in excess (in view of the compound of formula (IV)). Step (i) 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 toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofurane or 2-methyl tetrahydrofuran.

Therefore, the present invention relates to a process (P10), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’), (P7”), (P8) or (P9), wherein step (ii) is carried without any solvent.

Therefore, the present invention relates to a process (P11), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’), (P7”), (P8) or (P9), wherein step (ii) is carried in at least one solvent.

Therefore, the present invention relates to a process (P11 ’), which is process (P11), wherein the least one solvent is a polar aprotic or apolar aprotic solvent.

Therefore, the present invention relates to a process (P11 ”), which is process (P11) or (P11 ’), wherein the solvent is chosen from the group consisting of toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofurane or 2-methyl tetrahydrofuran.

The step (ii) is usually carried out at a temperature of 10°C to 100° C. (preferably 20°C to 80° C).

Therefore, the present invention relates to a process (P12), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’), (P7”), (P8), (P9), (P10), (P11), (P11 ’) or (P11”), wherein step (ii) is carried out at a temperature of 10°C to 100° C.

Therefore, the present invention relates to a process (P12’), which is process (P), (P1), (P2), (P3), (P4), (P5), (P5’), (P6), (P6’), (P7), (P7’), (P7”), (P8), (P9), (P10), (P11), (P11 ’) or (P11”), wherein step (ii) is carried out at a temperature of 20°C to 80° C.

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

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

Furthermore the compounds of formula (I) are new.

Therefore the present invention also relates to compounds of formula (I)

wherein

Ri and R ₂ are independently of each other a linear or branched Ci - C ₆ alkyl group;

-NH ₂ ; -NO ₂ ; -OH; -OR ₄ ; or -CN, wherein R ₄ is a linear or branched Ci - C ₆ alkyl group, (preferably a linear or branched Ci-C ₄ alkyl group) or a Cs-Cy-cycloalkyl, n and m are independently of each other an integer having a value of 0 or 1 .

Preferably, the present invention also relates to compounds of formula (I) wherein

Ri and R ₂ are independently of each other Ci - C ₂ alkyl group; -NH ₂ ; -NO ₂ ; -OH; or

-OCH3, and n and m are independently of each other an integer having a value of 0 or 1 .

Furthermore, the present invention relates to the compound of formula (la) 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) in food, feed, pharma and personal care applications.

Preferably the present invention relates to the use of the compounds of formula (la) 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 :

Methyl (rac)-mandelate, 10.25 g (61.1 mmol), and 160 mg (3 mmol) ammonium chloride were added in a 500 ml autoclave and filled with 60 g anhydrous (gas) ammonia. The mixture was heated to 30°C and stirred at 1000 rpm and 10 bar for 20 h. The reaction was cooling to room temperature and the ammonia was removed.

The resulting reaction mixture was dissolved in isopropanol and methanol. The obtaining solution was evaporated under reduced pressure (10 mbar, 40°C).

9.44 g 2-hydroxy-2-phenylacetamide in a yield of 98% with a purity of 96.2% was obtained.

In a 50-ml four-necked flask equipped with a magnetic-stirrer, thermometer and a reflux condenser with an argon inlet, 1 g (6.28 mmol) 2-hydroxy-2-phenylacetamide, 18.08 ml (106.76) mmol butyric anhydride in the presence of 100 pl (1.23 mmol) pyridine was stirred at 400 rpm at 298 K for 20 h. The crude product was purified by column chromatography.

Silica gel 60 (0.063-0.200 mm), cyclohexane/ethyl acetate.

The pure product was isolated as white powder in 95.4 % purity.

Yield 925 mg 2-amino-2-oxo-1 -phenylethyl butyrate, 63.5 % based on (2-hydroxy-2- phenylacetamide).

Example 2:

Methyl (R)-2-hydroxy-2-phenylacetate, 10.25 g (59.8 mmol), and 160 mg (3 mmol) ammonium chloride were added in a 500 ml autoclave and filled with 60 g anhydrous (gas) ammonia. The mixture was heated to 30°C and stirred at 1000 rpm and 10 bar for 20 h. The reaction was cooling to room temperature and the ammonia was removed.

The resulting reaction mixture (white powder) was dried under reduced pressure (10 mbar, 40°C).

8.91 g (R)-2-hydroxy-2-phenylacetamide was obtained in a yield of 95% with a purity of 96.6%. In a 50-ml four-necked flask equipped with a magnetic-stirrer, thermometer and a reflux condenser with an argon inlet, 1 g (6.39 mmol) (R)-2-hydroxy-2-phenylacetamide, 18.08 ml (106.76) mmol butyric anhydride in the presence of 100 pl (1.23 mmol) pyridine was stirred at 400 rpm at 298 K for 20 h.

The crude product was purified by column chromatography.

The pure product was isolated as white powder in 96 % purity.

Yield 1.15 g (R)-2-amino-2-oxo-1 -phenylethyl butyrate, 78 % based on (R)-2-hydroxy-2- phenylacetamide.