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WO2023198486A1 - Composés de butyrate d'urolithine - Google Patents

Composés de butyrate d'urolithine Download PDF

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Publication number
WO2023198486A1
WO2023198486A1 PCT/EP2023/058610 EP2023058610W WO2023198486A1 WO 2023198486 A1 WO2023198486 A1 WO 2023198486A1 EP 2023058610 W EP2023058610 W EP 2023058610W WO 2023198486 A1 WO2023198486 A1 WO 2023198486A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
process according
base
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/058610
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English (en)
Inventor
Werner Bonrath
Roman IMHOF
Kun Peng
Liuhai WU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
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DSM IP Assets BV
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Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of WO2023198486A1 publication Critical patent/WO2023198486A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • 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.
  • butyrates fuels colonocytes 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.
  • 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.
  • GLP-1 glucagon-like peptide-1
  • PYY peptide YY
  • 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.
  • 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.
  • specific new butyrate compounds as defined by the formula below can be obtained in good yields by a new and easy process.
  • 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.
  • the present invention relates to a compound of formula (la)
  • the present invention relates to a compound of formula (lb)
  • the present invention relates to a compound of formula (Ic)
  • the present invention relates to a compound of formula (la)
  • the present invention relates to a compound of formula (lb)
  • 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).
  • 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.
  • X is a halogen (such as Cl, Br, or F), OH, or a group -O(CO)(CH 2 )2CH3.
  • the reaction is carried in the presence of at least one base.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a process (P1 ), which is process (P), wherein the process is carried without any solvent.
  • the present invention relates to a process (P2), which is process (P), wherein the process is carried in at least one inert solvent.
  • 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.
  • 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 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).
  • 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 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.
  • 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.
  • 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.
  • 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 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
  • 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)).
  • 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.
  • 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.
  • 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)
  • 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.
  • 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).
  • 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 relates to compounds of formula (I’) with the proviso that when R is H then Ri is not H.
  • the present invention also relates to a compound of formula (I’a)
  • the present invention also relates to a compound of formula (I’b)
  • the present invention also relates to a compound of formula (I’c)
  • 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.
  • 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.
  • MTBE methyl tert-butyl ether
  • 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%.
  • 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%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouveaux composés spécifiques de butyrate d'urolithine et la synthèse de ces butyrates d'urolithine spécifiques ainsi que de nouveaux composés et leur utilisation. Les composés de butyrate sont des composés très utiles, en tant que tels ou en tant qu'intermédiaires dans la synthèse organique.
PCT/EP2023/058610 2022-04-13 2023-04-03 Composés de butyrate d'urolithine Ceased WO2023198486A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022086527 2022-04-13
CNPCT/CN2022/086527 2022-04-13

Publications (1)

Publication Number Publication Date
WO2023198486A1 true WO2023198486A1 (fr) 2023-10-19

Family

ID=86053966

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/058610 Ceased WO2023198486A1 (fr) 2022-04-13 2023-04-03 Composés de butyrate d'urolithine

Country Status (1)

Country Link
WO (1) WO2023198486A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015100213A2 (fr) * 2013-12-23 2015-07-02 Amazentis Sa Synthese d'urolithines a echelle de procede
WO2020110089A1 (fr) * 2018-11-29 2020-06-04 Warszawski Uniwersytet Medyczny Urolithine a et composition la contenant pour utilisation externe dans des inflammations de diverses étiologies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015100213A2 (fr) * 2013-12-23 2015-07-02 Amazentis Sa Synthese d'urolithines a echelle de procede
WO2020110089A1 (fr) * 2018-11-29 2020-06-04 Warszawski Uniwersytet Medyczny Urolithine a et composition la contenant pour utilisation externe dans des inflammations de diverses étiologies

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