The present invention relates to 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 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 (I) wherein in a first step (step (i)) a compound of formula (II) is reacted with a compound of formula (III) and then in a second step (step (ii)) the reaction product of step (i) is hydrogenated selectively to form the compound of formula (I).

In the following the two reaction steps are discussed and described in more detail. Step (i)

As stated above in the first step the compound of formula (II) is reacted with a compound of formula (II)

The compound of formula (IV) is the reaction product of step (i), which is then hydrogenated in step (ii).

The reaction of step (i) is usually carried out in at least one inert solvent.

When using a solvent the solvent is usually a polar aprotic or a nonpolar aprotic solvent.

Suitable solvents are toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether or 2-methyl tetrahydrofuran.

Therefore, the present invention relates to a process (P1 ), which is process (P), wherein step (i) is carried in at least one solvent. Therefore, the present invention relates to a process (PT), which is process (P1 ), wherein the least one solvent is a polar aprotic or a nonpolar aprotic solvent.

Therefore, the present invention relates to a process (P1 ”), which is process (P1 ) or (PT), wherein the solvent is chosen from the group consisting of toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether or 2-methyl tetrahydrofuran.

Preferably the reaction of step (i) is carried in the presence of at least one further acid (next to the compound of formula (III)).

Such a further acid serves as a catalyst in the reaction according to the present invention.

Such a further acid is usually a strong acid (pKa value below 4). The acid can be a solid and/or a liquid acid.

Suitable liquid acids are i.e. H2SO4 H3PO4, HCI and p-TsOH. Suitable solid acid catalysts are i.e. Amberlyst 15, Amberlyst 16, Amberlyst 72, DOWEX 36, or polymer- p-TsOH.

The amount of the at least one further acid is 2 - 40 mol-% (in view of the compound of formula (II)).

Therefore, the present invention relates to a process (P2), which is process (P), (P1 ), (PT) or (P1”), wherein the reaction of step (i) is carried in the presence of at least one further acid (next to the compound of formula (III)).

Therefore, the present invention relates to a process (P2’), which is process (P2), wherein the at least one further acid is a strong acid, which has a pKa value below 4.

Therefore, the present invention relates to a process (P2”), which is process (P2) or (P2’), wherein the at least one further acid is chosen from the group consisting of H2SO4 H3PO4, HCI, p-TsOH, Amberlyst 15, Amberlyst 16, Amberlyst 72, DOWEX 36, or polymer-p-TsOH. Therefore, the present invention relates to a process (P2’”), which is process (P2), (P2’) or (P2”), wherein the amount of the at least one further acid is 2 - 40 mol-% (in view of the compound of formula (II)).

The reaction of step (i) is carried out at an elevated temperature.

Usually the temperature of the reaction of step (i) is 40 - 150° C (preferably 60 - 120° C).

Therefore, the present invention relates to a process (P3), which is process (P), (P1 ), (PT), (P1”), (P2), (P2’), (P2”) or (P2’”), wherein the reaction of step (i) is carried out at an elevated temperature.

Therefore, the present invention relates to a process (P3’), which is process (P3), wherein the reaction of step (i) is carried out at a temperature of 40 - 150° C.

Therefore, the present invention relates to a process (P3”), which is process (P3), wherein the reaction of step (i) is carried out at a temperature of 60 - 120° C.

Usually the compound of formula (III) is added in an excess in view of the compound of formula (II).

Preferably the molar ratio of the compound of formula (II) to compound of formula (III) is 1 :1.5. to 1 :10 (preferably 1 :2 to 1 :5).

Therefore, the present invention relates to a process (P4), which is process (P), (P1 ), (P1 ’), (P1 ”), (P2), (P2’), (P2”), (P2’”), (P3), (P3’) or (P3”), wherein step (i) the compound of formula (III) is added in an excess in view of the compound of formula

(II).

Therefore, the present invention relates to a process (P4’), which is process (P4), wherein step (i) the molar ratio of the compound of formula (II) to compound of formula

(III) is 1 :1.5. to 1 :10.

Therefore, the present invention relates to a process (P4”), which is process (P4), wherein step (i) the molar ratio of the compound of formula (II) to compound of formula (III) is 1 :2 to 1 :5. The reaction of step (i) is usually carried out for a few hours, (up to 2 days).

The reaction product of step (i), which is the compound of formula (IV) is usually isolated after the reaction of step (ii) is terminated.

The isolation is carried by using commonly known methods. Furthermore, the reaction product of step (i) can be purified.

Step (ii)

In the second step (step (ii)) the reaction product of step (i), which is the compound of formula (IV) is hydrogenated to form the compound of formula (I).

The hydrogenation of step (ii) is usually carried out with H2 gas. It can be pure H2 or H2 containing gas.

The hydrogenation of step (ii) is usually carried at elevated pressure. The pressure is usually 2 to 10 bar (preferably 3 to 8 bar). Therefore, the present invention relates to a process (P5), which is process (P), (P1 ), (P1’), (P1”), (P2), (P2’), (P2”), (P2’”), (P3), (P3’), (P3”), (P4), (P4’) or (P4”), wherein step (ii) the hydrogenation is carried out with H2 gas.

Therefore, the present invention relates to a process (P6), which is process (P), (P1 ), (PT), (P1”), (P2), (P2’), (P2”), (P2’”), (P3), (P3’), (P3”), (P4), (P4’), (P4”) or (P5), wherein step (ii) the hydrogenation is carried out at a pressure of 2 to 10 bar.

Therefore, the present invention relates to a process (P6’), which is process (P), (P1 ), (P1’), (P1”), (P2), (P2’), (P2”), (P2’”), (P3), (P3’), (P3”), (P4), (P4’), (P4”) or (P5), wherein step (ii) the hydrogenation is carried out at a pressure of 3 to 8 bar.

The hydrogenation of step (ii) is usually carried out in the presence of at least one catalyst.

The catalyst can be a Pd/support and/or Ni/support.

Preferably it is a heterogenous catalyst (such as Pd/A^Os, Pd/C, Pd/TiC ).

The catalyst in step (i) is usually used in an amount of 1 - 10 mol-% in view of the compound of formula (IV) (preferably 2 - 8 mol-% in view of the compound of formula (IV)).

The substrate to catalyst ratio is between 50 : 1000.

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

Therefore, the present invention relates to a process (P7’), which is process (P7), wherein the least one catalyst is a heterogenous catalyst.

Therefore, the present invention relates to a process (P7”), which is process (P7) or (P7’), wherein the at least one catalyst is chosen from the group consisting of Pd/support and or Ni/support. Therefore, the present invention relates to a process (P7’”), which is process (P7) or (P7’), wherein the at least one catalyst is chosen from the group consisting PCI/AI2O3, Pd/C and Pd/TiO ₂ .

Therefore, the present invention relates to a process (P7””), which is process (P7), (P7’), (P7”) or (P7’”), wherein the at least one catalyst is used in an amount of 1 - 10 mol-% in view of the compound of formula (IV).

The hydrogenation of step (ii) is usually carried out in at least one inert solvent.

When using a solvent the solvent is usually a polar aprotic or a nonpolar aprotic solvent.

Suitable solvents are toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether, or 2-methyl tetrahydrofuran.

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

Therefore, the present invention relates to a process (P8’), which is process (P8), wherein the least one solvent is a polar aprotic or a nonpolar aprotic solvent.

Therefore, the present invention relates to a process (P8”), which is process (P8) or (PT), wherein the solvent is chosen from the group consisting of toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether, or 2-methyl tetrahydrofuran.

The hydrogenation of step (ii) is carried out at a temperature of 25 - 100° C (preferably 30 - 80° C). Therefore, the present invention relates to a process (P9), which is process (P), (P1 ), (P1’), (P1 ”), (P2), (P2’), (P2”), (P2”’), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P5), (P6), (P6’), (P7), (P7’), (P7”), (P7’”), (P7””), (P8), (P8’) or (P8”), wherein step (ii) is carried at a temperature of 25 - 100°C.

Therefore, the present invention relates to a process (P9’), which is process (P), (P1 ), (PT), (P1 ”), (P2), (P2’), (P2”), (P2”’), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P5), (P6), (P6’), (P7), (P7’), (P7”), (P7’”), (P7””), (P8), (P8’) or (P8”), wherein step (ii) is carried at a temperature of 30 - 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.

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 :

In a 50-ml four-necked flask equipped with a magnetic-stirrer, thermometer, water separator and a reflux condenser with an argon inlet, 1 .69 g (11 .14 mmol) 2-isopropyl- 5-methylphenol and 4.20 g (47.8 mmol) crotonyl acid were dissolved in 40 ml toluene in the presence of 94 pl (15 mol%, 1.696 mmol) H2SO4 (96.7%). The mixture was stirred at 400 rpm and heated at 383 K (internal temperature) for 30 h. The mixture was dissolved in 40 ml toluene and washed 1 time with 20 ml 10% NaOH and 3 times with 20 ml H2O and dried with sodium sulfate and evaporated under reduced pressure (10 mbar, 313 K). The crude product was isolated as light yellowish liquid in 91.3 % purity (q-NMR).

Yield 2.09 g 2-isopropyl-5-methylphenyl (E)-but-2-enoate, 95 % based on 2-isopropyl- 5-methylphenol.

In a 16-ml flask equipped with a magnetic-stirrer, 2.09 g (8.74 mmol) 2-isopropyl-5- methylphenyl (E)-but-2-enoate, 130 mg catalyst 5% Pd/A^Os and 6 g toluene were mixed. The reaction mixture was purged 3 times with nitrogen (pressurize to 5 bar and release). The mixture was heated to 313 K and then pressurized to 5 bar with hydrogen gas. The mixture was stirred at 500 rpm at 313 K jacket temperature for 2 h. The mixture was cooled to room temperature and the pressure was released. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure (10 mbar, 313 K). The crude product was isolated as colorless-light yellowish liquid in 93.6 % purity (q-NMR).

Yield 1.95 g 2-isopropyl-5-methylphenyl butyrate, 95 % based on 2-isopropyl-5- methylphenyl (E)-but-2-enoate.