IMHOF ROMAN (CH)
PENG KUN (CH)
WU LIUHAI (CH)
| WO2015100213A2 | 2015-07-02 | |||
| WO2020110089A1 | 2020-06-04 |
| Claims 1. A compound of formula (I) wherein R is H or -CH2(CO)CH2CH2CH3 AND Ri is H or -CH2(CO)CH2CH2CH3 with the proviso that when R is H then Ri is not H. 2. Process for producing compounds of formula (I) according to claim 1 , wherein the compound of formula (II) is reacted with a compound of formula (III) wherein X is a halogen (such as Cl, Br, or F) or a group -O(CO)(CH2)2CH3. 3. Process according to claim 2, wherein the process is carried without any solvent. 4. Process according to claim 2, wherein the process is carried out in at least one inert solvent. 5. Process according to claim 4, wherein the solvent is a is a polar aprotic or non-polar solvent. 6. Process according to claim 4, wherein the solvent is chosen from the group consisting of pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene. 7. Process according to any of claims 2 - 6, wherein the process is carried out in the presence of at least one base. 8. Process according to claim 7, wherein the base is a nitrogen containing base. 9. Process according to claim 7, wherein the base is chosen from the group consisting of pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine), Na2CO3, K2CO3, NaOH, CaO, La2O3, lanthanoid carbonates (such as La2(CO3)2), CaCO3 and KF/AI2O3. 10. Process according to any of claims 7 - 9, wherein the at least one base is used in a molar ratio of 1 :1 to 1 :100 in view of the compound of formula (II). 11. Process according to any of claims 2 - 10, wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is 1 :1 to 2:1 , when one OH group in the compound of formula (II) is to be acetylated. 12. Process according to any of claims 2 - 10, wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is 2:1 to 10:1 , when two OH groups in the compound of formula (II) are to be acetylated. 13. Process according to any of claims 2 - 12, wherein the process is carried out at a temperature of -10°C to 50° C. 14. Compounds of formula (I’) with the proviso that when R is H then Ri is not H. 15. Compound of formula (I’a) 17. Compound of formula (I’c) |
The present invention relates to new specific Urolithin butyrate compounds and to the synthesis of these specific Urolithin 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 other useful 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 mentioned above in a good yield and avoiding the disadvantages such as having a strong unpleasant odour. 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 compound of formula (I) wherein
R is H or -CH 2 (CO)CH 2 CH 2 CH 3
RI is H or -CH 2 (CO)CH 2 CH 2 CH 3 with the proviso that when R is H then Ri is not H.
Preferably, the present invention relates to a compound of formula (la)
Preferably, the present invention relates to a compound of formula (lb)
Preferably, the present invention relates to a compound of formula (Ic)
Therefore, the present invention relates to a compound of formula (la)
Therefore, the present invention relates to a compound of formula (lb)
Therefore, the present invention relates to a compound of formula (lc)
The new compounds according to the can be produced the following way:
The starting material is the compound of formula (II) which is Urolithin A (also known as 3,8-dihydroxy-6H-benzo[c]chromen-6-one or 3,8- dihydroxy-6H-dibenzo[b,d]pyran-6-one).
The compound of formula (II) is then reacted with a compound of formula (III) wherein X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH 2 )2CH3.
Preferably, the reaction is carried in the presence of at least one base.
Therefore, the present invention relates to a process (P) for producing the compounds of formula (I) wherein
R is H or -CH 2 (CO)CH 2 CH 2 CH 3
RI is H or -CH 2 (CO)CH 2 CH 2 CH 3 with the proviso that when R is H then Ri is not H, wherein the compound of formula (II) is reacted with a compound of formula (III) wherein
X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH2)2CH3.
The reaction can be carried out without any solvents or in an inert solvent (or mixture of inert solvents) and preferably in the presence of at least one base.
As stated above 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 as well as non-polar solvent.
Suitable solvents are i.e. pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene as well as mixture thereof.
Therefore, the present invention relates to a process (P1 ), which is process (P), wherein the process is carried without any solvent.
Therefore, the present invention relates to a process (P2), which is process (P), wherein the process is carried in at least one inert solvent.
Therefore, the present invention relates to a process (P2’), which is process (P2), wherein the solvent (or the mixture of solvents) is a polar aprotic or non-polar solvent.
Therefore, the present invention relates to a process (P2”), which is process (P2), wherein the solvent is chosen from the group consisting of pyridine, picolines, dichloromethane, trichloromethane, ketones, acetonitrile, xylene, and toluene.
The process according to the present invention is carried out in the presence of at least one base. The base can be an organic or an inorganic base.
Suitable organic bases are nitrogen containing bases, such as pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine).
Suitable inorganic bases (catalysts) are Na2COs, K2CO3, NaOH, CaO, La2Os, lanthanoid carbonates (such as La2(COs)2), CaCCh and KF/AI2O3.
The inorganic bases serve as catalyst in the reaction.
The nitrogen containing base can serve as solvent as well as well as a catalyst.
Therefore, the present invention relates to a process (P3), which is process (P), (P1), (P2), (P2’) or (P2”), wherein the process is carried out in the presence of at least one base.
Therefore, the present invention relates to a process (P3’), which is process (P3), wherein the base is an organic or an inorganic base. Therefore, the present invention relates to a process (P3”), which is process (P3’), wherein the organic base is a nitrogen containing base.
Therefore, the present invention relates to a process (P3’”), which is process (P3), (P3’) or (P3”), wherein the base is chosen from the group consisting of pyrimidine, pyridines, picoline purine, 4-dimethylaminopyridine, imidazoles (such as methylimidazole) or trialkyl amines, (e.g. triethyl amine, tributylamine or diisopropylethyl amine), Na2COs, K2CO3, NaOH, CaO, La2Os, lanthanoid carbonates (such as La2(COs)2), CaCCh and KF/AI2O3.
The total amount of base, which is added to the reaction mixture, is in a molar ratio of 1 :1 to 1 :100 in view of the compound of formula (II), preferably 1 :1 to 1 :50.
The bases used as catalysts are added are added in small amounts (in view of the compound of formula (II)).
Therefore, the present invention relates to a process (P3’”), which is process (P3), (P3’) or (P3”), wherein the at least one base is used in a molar ratio of 1 :1 to 1 : 100 in view of the compound of formula (II).
The compound of formula (III) is used in excess in view of the compound of formula (II). It is clear that when two OH groups in compounds of formula (II) 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 (III) to the compound of formula (II) is 1 :1 to 2:1 , when one OH group in the compound of formula (II) is to be acetylated.
The molar ratio of the compound of formula (III) to the compound of formula (II) is at least 2:1 (preferably 2:1 to 10:1 , more preferably 2:1 to 5:1), when two OH groups in the compound of formula (II) are to be acetylated.
Therefore, the present invention relates to a process (P4), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”) or (P3’”), wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is 1 :1 to 2:1 , when one OH group in the compound of formula (II) is to be acetylated.
Therefore, the present invention relates to a process (P4’), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”) or (P3’”), wherein the molar ratio of the compound of formula (III) to the compound of formula (II) is at least 2:1 (preferably 2:1 to 10:1 , more preferably 2:1 to 5:1), when two OH groups in the compound of formula (II) are to be acetylated.
The process according to the present invention is carried out at a temperature of -10°C to 50° C. (preferably -10°C - 40°C, -5°C - 30°C)
Therefore, the present invention relates to a process (P5), which is process (P), (P1), (P2), (P2’), (P2”), (P3), (P3’), (P3”), (P3’”), (P4) or (P4’), wherein the process is carried out at a temperature of -10°C to 50° C.
Alternatively, it is also possible to produce the compound of formula (I) as follows
The starting material is the compound of formula (I) and it is reacted with a compound of formula (IV) forming a compound of formula (I’) with the proviso that when R is H then Ri is not H, which is then in a further step hydrogenated (using commonly known methods) to the compound of formula (I).
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.
Furthermore, the present invention relates to compounds of formula (I’) with the proviso that when R is H then Ri is not H.
Therefore, the present invention also relates to a compound of formula (I’a)
Therefore, the present invention also relates to a compound of formula (I’b)
Therefore, the present invention also relates to a compound of formula (I’c)
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. 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 :
To a suspension of 228 mg Urolithin A (1 mmol, 1 eq) in 3 mL pyridine 6 mg 4- dimethylaminopyridine (DMAP) (0.05 mmol, 0.05 eq) was added at room temperature. The reaction mixture was cooled to 0°C and 475 mg of butyric anhydride (3 mmol, 3 eq) was added.
Once the addition was completed, the reaction mixture was heated to room temperature and kept stirring for a few hours, and 20 mL water was added and the suspension was filtered under vacuum.
The filter cake was washed with 5 mL methyl tert-butyl ether (MTBE) and further dried under vacuum.
The yield of the compound of formula (la) was 83%.
Example 2:
To a suspension of 228 mg of Urolithin A (1 mmol, 1 eq) in 3 mL toluene in a 10 mL vial at rt. To this suspension, 6 mg of 4-dimethylaminopyridine (DMAP) (0.05 mmol, 0.05 eq), 304 mg of triethylamine (3 mmol, 3 eq) were added.
The reaction mixture was cooled to 0°C and 234 mg of butyric chloride (2.2 mmol, 2.2 eq) was added
Once the addition was completed, the reaction mixture was heated to room temperature and kept stirring for a few hours, and 20 mL water was added to the mixture and the suspension was filtered under vacuum.
The filter cake was washed with 5 mL methyl tert-butyl ether (MTBE) and further dried. The yield of the compound of formula (la) was 70%.
Example 3:
To a suspension of 228 mg of Urolithin A (1 mmol, 1 eq) in 3 mL of dichloromethane (DCM) 194 mg of butyric acid (2.2 mmol, 2.2 eq), 423 mg of N,N'- dicyclohexylcarbodiimide (DCC) (2.05 mmol, 2.05 eq), and 6 mg of 4- dimethylaminopyridine (DMAP) (0.05 mmol, 0.05 eq) were added.
Once the addition was completed, the reaction mixture was kept stirring for a few hours.
The reaction mixture was concentrated under vacuum.
The yield of the compound of formula (la) was 75%.