WO2023078722A1 - Synthesis of pantothenic acid butyrate - Google Patents

Synthesis of pantothenic acid butyrate Download PDF

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WO2023078722A1
WO2023078722A1 PCT/EP2022/079685 EP2022079685W WO2023078722A1 WO 2023078722 A1 WO2023078722 A1 WO 2023078722A1 EP 2022079685 W EP2022079685 W EP 2022079685W WO 2023078722 A1 WO2023078722 A1 WO 2023078722A1
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compound
process according
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PCT/EP2022/079685
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Werner Bonrath
Christophe EGGERTSWYLER
Francesco Pace
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Dsm Ip Assets B.V.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • 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 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 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.
  • butyrates 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 selectivity by a new and efficient process.
  • the present invention relates to a process (P) for producing a compound of formula (I) wherein Ri is a Ci - Ce-alkyl moiety (preferably a Ci - C4-alkyl moiety, more preferably a C-i- C2-alkyl moiety), and the * marks the chiral centre, 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 (V) and then in a third step (step (iii) the compound of formula (IV) is reacted with a compound of formula (VI) wherein R has the same meanings as defined for the compound of formula (I) to form the compound of formula (I).
  • Ri is a Ci - Ce-alkyl moiety (preferably a Ci - C4-alkyl moiety, more preferably a C-i-
  • the present invention relates to a process (P’), which is the process (P), wherein Ri is a Ci - C4-alkyl moiety.
  • the present invention relates to a process (P”), which is the process (P), wherein Ri is a Ci - C2-alkyl moiety.
  • the absolute configuration does not change during the chemical process.
  • the present invention relates to a process (P1 ), which is the process (P), (P’) or (P”), wherein the compound of formula (Ila) is used.
  • the present invention relates to a process (PT), which is the process (P), (P’) or (P”), wherein the compound of formula (lib) is used. Therefore, the present invention relates to a process (P1 ”), which is the process (P) (P), (P’) or (P”), wherein a mixture of the compounds of formula (Ila) and of formula (Hb) is used.
  • the present invention relates to a process (P2), which is the process (P1 ”), wherein the mixture of the compounds of formula (Ila) and of formula (lib) is a 1 :1 mixture.
  • step (i) is usually carried out in at least one inert solvent.
  • the solvent is usually a polar aprotic or non-polar aprotic solvent.
  • Suitable solvents are toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether, or 2-methyl tetrahydrofuran.
  • the present invention relates to a process (P3), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”) or (P2), wherein step (i) is carried in at least one inert solvent.
  • the present invention relates to a process (P3’), which is process (P3), wherein the least one solvent is a polar aprotic or non-polar aprotic solvent.
  • the present invention relates to a process (P3”), which is process (P3) or (P3’), 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 solvent is chosen from the group consisting of toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether, or 2-methyl tetrahydrofuran.
  • step (i) is carried in the presence of at least one further acid (next to the compound of formula (III)).
  • This acid is usually a strong acid (pKa value below 4)
  • Such acids are i.e. H2SO4, H3PO4, HCI, p-TsOH, polymer-p-TsOH, solid acids such as ion exchange resins, i.e. Amberlyst type (DOWEX, Amerlyst 15).
  • the amount of the at least one further acid is 0.1 - 50 mol-%, preferred 1 -40 mol-% (in view of the compound of formula (II)).
  • the present invention relates to a process (P4), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’) or (P3”), wherein the reaction of step (i) is carried in the presence of at least one further acid (next to the compound of formula (HI)).
  • the present invention relates to a process (P4’), which is process (P4), wherein the at least one further acid is a strong acid, which has a pKa value below 4.
  • the present invention relates to a process (P4”), which is process (P4) or (P4’), wherein the at least one further acid is chosen from the group consisting of H2SO4, H3PO4, HCI, p-TsOH, polymer-p-TsOH, solid acids such as ion exchange resins, i.e. Amberlyst type (DOWEX, Amerlyst 15).
  • P4 process (P4) or (P4’)
  • the at least one further acid is chosen from the group consisting of H2SO4, H3PO4, HCI, p-TsOH, polymer-p-TsOH, solid acids such as ion exchange resins, i.e. Amberlyst type (DOWEX, Amerlyst 15).
  • the present invention relates to a process (P4’”), which is process (P4), (P4’) or (P4”), wherein the amount of the at least one further acid is 0.1 - 50 mol-% (in view of the compound of formula (II)).
  • the present invention relates to a process (P4””), which is process (P4), (P4’) or (P4”), wherein the amount of the at least one further acid is 1 - 40 mol-% (in view of the compound of formula (II)).
  • step (i) is carried out at an elevated temperature.
  • the temperature of the reaction of step (i) is between 40 - 150° C (preferably between 60 - 120° C). Therefore, the present invention relates to a process (P5), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”) or (P4””), wherein the reaction of step (i) is carried out at an elevated temperature.
  • the present invention relates to a process (P5’), which is process (P5), wherein the reaction of step (i) is carried out at a temperature of 40 - 150° C.
  • the present invention relates to a process (P5”), which is process (P5), wherein the reaction of step (i) is carried out at a temperature of 60 - 120° C.
  • 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).
  • the present invention relates to a process (P6), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4’”) (P5”), wherein step (i) the compound of formula (III) is added in an excess in view of the compound of formula (II).
  • the present invention relates to a process (P6’), which is process (P6), wherein step (i) the molar ratio of the compound of formula (II) to compound of formula (III) is 1 :1.5. to 1 :10.
  • the present invention relates to a process (P6”), which is process (P6), wherein step (i) the molar ratio of the compound of formula (II) to compound of formula (III) is 1 :2 to 1 :5.
  • step (i) is usually carried out for a few hours, (up to 2 days).
  • step (i) which is the compound of formula (IV) is usually isolated after the reaction of step (ii) is terminated.
  • step (i) The isolation is carried by using commonly known methods. Furthermore, the reaction product of step (i) can be purified.
  • step (ii) the reaction product of step (i), which is the compound of formula (IV) is hydrogenated to form the compound of formula (I).
  • step (ii) is usually carried out with H 2 gas. It can be pure H 2 or H 2 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).
  • the present invention relates to a process (P7), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’), (P4’’’), (P4’’’), (P4’’’), (P5), (P5’), (P5’’), (P6), (P6’) or (P6’’), wherein step (ii) the hydrogenation is carried out with H2 gas.
  • the present invention relates to a process (P8), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’), (P4’’’), (P4’’’), (P4’’’), (P5), (P5’), (P5’’), (P6), (P6’), (P6’’) or (P7), wherein step (ii) the hydrogenation is carried out at a pressure of 2 to 10 bar.
  • the present invention relates to a process (P8’), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’), (P4’’’), (P4’’’), (P4’’’), (P5), (P5’), (P5’’), (P6), (P6’), (P6’’) or (P7), 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. Preferably it is a heterogenous catalyst.
  • the catalyst can be selected from supported Pd on a carrier, such as Pd/C, Pd/SiO 2 , Pd/Al 2 O 3, Pd/TiO 2 , Pd/CeO 2 or Pd/BaSO 4 . Most preferably the catalyst is Pd/Al2O3.
  • 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.
  • the present invention relates to a process (P9), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5”), (P5”), (P6), (P6’), (P6”), (P7), (P8) or (P8’), wherein step (ii) is carried out in the presence of at least one catalyst.
  • the present invention relates to a process (P9’), which is process (P9), wherein the at least one catalyst is a heterogenous catalyst.
  • the present invention relates to a process (P9”), which is process (P9) or (P9’), wherein the at least one catalyst is supported Pd on a carrier (such as Pd/C, Pd/SiO 2 , Pd/AI 2 O 3 , Pd/TiO 2 , Pd/CeO 2 or Pd/BaSO 4 ).
  • a carrier such as Pd/C, Pd/SiO 2 , Pd/AI 2 O 3 , Pd/TiO 2 , Pd/CeO 2 or Pd/BaSO 4 .
  • the present invention relates to a process (P9’”), which is process (P9), (P9’) or (P9”), wherein the at least one catalyst is Pd/AI 2 O 3 .
  • the present invention relates to a process (P9””), which is process (P9), (P9’), (P9”) or (P9’”), wherein the at least one catalyst is used in an amount of 1 - 10 mol-% in view of the compound of formula (IV).
  • step (ii) is usually carried out in at least one inert solvent.
  • the solvent is usually a polar aprotic or nonpolar aprotic solvent.
  • Suitable solvents are toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether or 2-methyl tetrahydrofuran.
  • the present invention relates to a process (P10), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”) or (P9’”), wherein step (ii) is carried in at least one solvent. Therefore, the present invention relates to a process (P1 O’), which is process (P8), wherein the least one solvent is a polar aprotic or nonpolar aprotic solvent.
  • the present invention relates to a process (P10”), which is process (P10) or (P1 O’), 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 solvent is chosen from the group consisting of toluene, xylene, cyclohexane, ethers (such as diethyl ether), tetrahydrofuran, cyclopentyl methyl ether or 2-methyl tetrahydrofuran.
  • step (ii) is carried out at a temperature of 25 - 100°C (preferably 30 - 80° C).
  • the present invention relates to a process (P11 ), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5”), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’) or (P10”), wherein step (ii) is carried at a temperature of 25 - 100° C.
  • the present invention relates to a process (P1 T), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5”), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’) or (P10”), wherein step (ii) is carried at a temperature of 30 - 80°C.
  • step (iii) the reaction product of step (ii), which is compound of formula (V) is reacted with the compound of formula (VI) wherein R (and Ri ), have the same meanings as defined above, to form the final product, which is the compound of formula (I) wherein R (and Ri ), have the same meanings as defined above.
  • R (as well as a mixture of both configurations); also here R (and Ri), have the same meanings as defined above.
  • step (iii) can be carried without any inert solvent.
  • the present invention relates to a process (P12), which is process (P), (P’), (P”), (P1 ), (PT), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ) or (P11 ’), wherein step (iii) is carried out without any solvents.
  • step (iii) can be carried in at least one inert solvent. Therefore, the present invention relates to a process (P13), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5”), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P1 O’), (P10”), (P11 ) or (P11 ’), wherein step (iii) is carried in the presence of at least one inert solvent.
  • step (iii) is carried in the presence of at least one inert solvent.
  • step (iii) is usually carried out at elevated temperatures. Usually and preferably the reaction of step (iii) is carried at a temperature of 40 - 150° C (more preferably 50 - 120° C).
  • the present invention relates to a process (P14), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ), (P1 T), (P12) or (P13), wherein step (ii) is carried at a temperature of 40
  • the present invention relates to a process (P14’), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ), (P1 T), (P12) or (P13), wherein step (ii) is carried at a temperature of 50
  • the present invention also relates to the compound of formula (I) , wherein R 1 is a C 1 – C 6 -alkyl moiety, and the * marks the chiral centre. Therefore, the present invention also relates to the compound of formula (I) , wherein R1 is a C1 – C4-alkyl moiety, and the * marks the chiral centre. Therefore, the present invention also relates to the compound of formula (I) , wherein R 1 is a C 1 - C 2 -alkyl moiety, and the * marks the chiral centre. Furthermore, the present invention also relates to the compounds of formula (Ia) , wherein R 1 is a C 1 – C 6 -alkyl moiety.
  • the present invention also relates to the compounds of formula (Ia) , wherein R 1 is a C 1 – C 4 -alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ia) , wherein R 1 is a C 1 – C 2 -alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ib) , wherein R 1 is a C 1 – C 6 -alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ib) , wherein R 1 is a C 1 – C 4 -alkyl moiety.
  • the present invention also relates to the compounds of formula (Ib) , wherein R 1 is a C 1 – C 2 -alkyl moiety.
  • R 1 is a C 1 – C 2 -alkyl moiety.
  • 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, 1.47 g (11.18 mmol) (R)-3-hydroxy-4,4- dimethyldihydrofuran-2(3H)-one and 4.20 g (47.8 mmol) crotonyl acid were dissolved in 40 ml toluene in the presence of 94 ⁇ l (15 mol%, 1.696 mmol) H2SO4 (96.7%). The mixture was stirred at 400 rpm and heated at 383 K (internal temperature) for 18 h.
  • Example 2 In a 55-ml flask equipped with a magnetic-stirrer, 2.02 g (10.13 mmol) (R)-4,4-dimethyl-2- oxotetrahydrofuran-3-yl (E)-but-2-enoate, 400 mg catalyst 5% Pd/Al2O3 and 20 ml 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 3 h. The mixture was cooled to room temperature and the pressure was released.
  • Example 3 In a 55-ml flask equipped with a magnetic-stirrer, 2.07 g (10.13 mmol) 4,4-dimethyl-2- oxotetrahydrofuran-3-yl (E)-but-2-enoate, 400 mg catalyst 5% Pd/Al 2 O 3 and 20 ml 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 3 h. The mixture was cooled to room temperature and the pressure was released.
  • Example 4 In a 5-ml round bottom flask equipped with a magnetic-stirrer and a reflux condenser, 500 mg (2.415 mmol) (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate (from Example 2) and 191 ml (2.462 mmol) 3-aminopropan-1-ol was stirred at 500 rpm at 373 K (oil temperature) for 1 h. The mixture was cooled to room temperature and analyzed without further purification. The crude product was isolated as a viscose colorless liquid in 91 % purity (Area-%).
  • Example 5 In a 5-ml round bottom flask equipped with a magnetic-stirrer and a reflux condenser, 500 mg (2.462 mmol) (R,S)4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate (from Example 3) and 191 ml (2.462 mmol) 3-aminopropan-1-ol was stirred at 500 rpm at 373 K (oil temperature) for 1 h. The mixture was cooled to room temperature and analyzed without further purification. The crude product was isolated as a viscose colorless liquid in 93.2% purity (Area-%).

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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.

Description

Synthesis of pantothenic acid butyrate
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.
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 selectivity by a new and efficient process.
Therefore, the present invention relates to a process (P) for producing a compound of formula (I)
Figure imgf000003_0003
wherein Ri is a Ci - Ce-alkyl moiety (preferably a Ci - C4-alkyl moiety, more preferably a C-i- C2-alkyl moiety), and the * marks the chiral centre, wherein in a first step (step (i)) a compound of formula (II)
Figure imgf000003_0001
is reacted with a compound of formula (III)
Figure imgf000003_0002
and then in a second step (step (ii)) the reaction product of step (i) is hydrogenated selectively to form the compound of formula (V)
Figure imgf000004_0002
and then in a third step (step (iii) the compound of formula (IV) is reacted with a compound of formula (VI)
Figure imgf000004_0003
wherein R has the same meanings as defined for the compound of formula (I) to form the compound of formula (I).
Therefore the present invention relates to a process (P’), which is the process (P), wherein Ri is a Ci - C4-alkyl moiety.
Therefore the present invention relates to a process (P”), which is the process (P), wherein Ri is a Ci - C2-alkyl moiety.
The * marks the chiral center in the chemical formula. This means that this compound have either R or S absolute configuration or the compound can be in a R/S mixture (in any ratio).
The absolute configuration does not change during the chemical process.
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)
Figure imgf000004_0001
is reacted with a compound of formula (III)
Figure imgf000005_0001
As stated above the compound of formula (II) has a chiral center. This means that the compound of formula can be in the R or S configuration, which is shown below as compounds of formula (Ila) and of formula (lib)
Figure imgf000005_0002
Also mixture of compound of formula (Ila) and of formula (lib) can be used.
Therefore, the present invention relates to a process (P1 ), which is the process (P), (P’) or (P”), wherein the compound of formula (Ila)
Figure imgf000005_0003
is used.
Therefore, the present invention relates to a process (PT), which is the process (P), (P’) or (P”), wherein the compound of formula (lib)
Figure imgf000005_0004
is used. Therefore, the present invention relates to a process (P1 ”), which is the process (P) (P), (P’) or (P”), wherein a mixture of the compounds of formula (Ila) and of formula (Hb)
Figure imgf000006_0001
is used.
Therefore, the present invention relates to a process (P2), which is the process (P1 ”), wherein the mixture of the compounds of formula (Ila) and of formula (lib) is a 1 :1 mixture.
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 non-polar 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 (P3), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”) or (P2), wherein step (i) is carried in at least one inert solvent.
Therefore, the present invention relates to a process (P3’), which is process (P3), wherein the least one solvent is a polar aprotic or non-polar aprotic solvent.
Therefore, the present invention relates to a process (P3”), which is process (P3) or (P3’), 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)). This acid is usually a strong acid (pKa value below 4)
Such acids are i.e. H2SO4, H3PO4, HCI, p-TsOH, polymer-p-TsOH, solid acids such as ion exchange resins, i.e. Amberlyst type (DOWEX, Amerlyst 15).
The amount of the at least one further acid is 0.1 - 50 mol-%, preferred 1 -40 mol-% (in view of the compound of formula (II)).
Therefore, the present invention relates to a process (P4), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’) or (P3”), wherein the reaction of step (i) is carried in the presence of at least one further acid (next to the compound of formula (HI)).
Therefore, the present invention relates to a process (P4’), which is process (P4), 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 (P4”), which is process (P4) or (P4’), wherein the at least one further acid is chosen from the group consisting of H2SO4, H3PO4, HCI, p-TsOH, polymer-p-TsOH, solid acids such as ion exchange resins, i.e. Amberlyst type (DOWEX, Amerlyst 15).
Therefore, the present invention relates to a process (P4’”), which is process (P4), (P4’) or (P4”), wherein the amount of the at least one further acid is 0.1 - 50 mol-% (in view of the compound of formula (II)).
Therefore, the present invention relates to a process (P4””), which is process (P4), (P4’) or (P4”), wherein the amount of the at least one further acid is 1 - 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 between 40 - 150° C (preferably between 60 - 120° C). Therefore, the present invention relates to a process (P5), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”) or (P4””), wherein the reaction of step (i) is carried out at an elevated temperature.
Therefore, the present invention relates to a process (P5’), which is process (P5), wherein the reaction of step (i) is carried out at a temperature of 40 - 150° C.
Therefore, the present invention relates to a process (P5”), which is process (P5), 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 (P6), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4’”) (P5), (P5’) or (P5”), 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 (P6’), which is process (P6), 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 (P6”), which is process (P6), 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)
Figure imgf000009_0003
is usually isolated after the reaction of step (ii) is terminated.
It is clear that the compound of formula (IV) can be in the R or in the S configuration
(compounds of formula (IVa) and of formula (IVb))
Figure imgf000009_0001
(as well as in a mixture of both configuration).
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)
Figure imgf000009_0002
is hydrogenated to form the compound of formula (I).
As stated before, the compound of formula (IV) exists in the R or in the S configuration (compounds of formula (IVa) and of formula (IVb)
Figure imgf000010_0001
(as well as a mixture of both configurations). 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 (P7), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’’), (P4’’’’), (P5), (P5’), (P5’’), (P6), (P6’) or (P6’’), wherein step (ii) the hydrogenation is carried out with H2 gas. Therefore, the present invention relates to a process (P8), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’’), (P4’’’’), (P5), (P5’), (P5’’), (P6), (P6’), (P6’’) or (P7), wherein step (ii) the hydrogenation is carried out at a pressure of 2 to 10 bar. Therefore, the present invention relates to a process (P8’), which is process (P), (P’), (P’’), (P1), (P1’), (P1’’), (P2), (P3), (P3’), (P3’’), (P4), (P4’), (P4’’), (P4’’’), (P4’’’’), (P5), (P5’), (P5’’), (P6), (P6’), (P6’’) or (P7), 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. Preferably it is a heterogenous catalyst. The catalyst can be selected from supported Pd on a carrier, such as Pd/C, Pd/SiO2, Pd/Al2O3, Pd/TiO2, Pd/CeO2 or Pd/BaSO4. Most preferably the catalyst is Pd/Al2O3. 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 (P9), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8) or (P8’), wherein step (ii) is carried out in the presence of at least one catalyst.
Therefore, the present invention relates to a process (P9’), which is process (P9), wherein the at least one catalyst is a heterogenous catalyst.
Therefore, the present invention relates to a process (P9”), which is process (P9) or (P9’), wherein the at least one catalyst is supported Pd on a carrier (such as Pd/C, Pd/SiO2, Pd/AI2O3, Pd/TiO2, Pd/CeO2 or Pd/BaSO4).
Therefore, the present invention relates to a process (P9’”), which is process (P9), (P9’) or (P9”), wherein the at least one catalyst is Pd/AI2O3.
Therefore, the present invention relates to a process (P9””), which is process (P9), (P9’), (P9”) or (P9’”), 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 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 (P10), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”) or (P9’”), wherein step (ii) is carried in at least one solvent. Therefore, the present invention relates to a process (P1 O’), which is process (P8), wherein the least one solvent is a polar aprotic or nonpolar aprotic solvent.
Therefore, the present invention relates to a process (P10”), which is process (P10) or (P1 O’), 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 (P11 ), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’) or (P10”), wherein step (ii) is carried at a temperature of 25 - 100° C.
Therefore, the present invention relates to a process (P1 T), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’) or (P10”), wherein step (ii) is carried at a temperature of 30 - 80°C.
Step (iii)
In step (iii), the reaction product of step (ii), which is compound of formula (V)
Figure imgf000012_0002
is reacted with the compound of formula (VI)
Figure imgf000012_0001
wherein R (and Ri ), have the same meanings as defined above, to form the final product, which is the compound of formula (I)
Figure imgf000013_0001
wherein R (and Ri ), have the same meanings as defined above.
As stated before, the compound of formula (I) exists in the R or in the S configuration (compounds of formula (la) and of formula (lb)
Figure imgf000013_0002
(as well as a mixture of both configurations); also here R (and Ri), have the same meanings as defined above.
The reaction of step (iii) can be carried without any inert solvent.
Therefore, the present invention relates to a process (P12), which is process (P), (P’), (P”), (P1 ), (PT), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ) or (P11 ’), wherein step (iii) is carried out without any solvents.
The reaction of step (iii) can be carried in at least one inert solvent. Therefore, the present invention relates to a process (P13), which is process (P), (P’), (P”), (P1 ), (PT), (P1 ”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P1 O’), (P10”), (P11 ) or (P11 ’), wherein step (iii) is carried in the presence of at least one inert solvent.
The reaction of step (iii) is usually carried out at elevated temperatures. Usually and preferably the reaction of step (iii) is carried at a temperature of 40 - 150° C (more preferably 50 - 120° C).
Therefore, the present invention relates to a process (P14), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ), (P1 T), (P12) or (P13), wherein step (ii) is carried at a temperature of 40
- 150° C.
Therefore, the present invention relates to a process (P14’), which is process (P), (P’), (P”), (P1 ), (P1 ’), (P1”), (P2), (P3), (P3’), (P3”), (P4), (P4’), (P4”), (P4’”), (P4””), (P5), (P5’), (P5”), (P6), (P6’), (P6”), (P7), (P8), (P8’), (P9), (P9’), (P9”), (P9’”), (P10), (P10’), (P10”), (P11 ), (P1 T), (P12) or (P13), wherein step (ii) is carried at a temperature of 50
- 120° C.
At the end of the reaction process the product (compounds of formula (I)) is isolated using commonly known methods.
The product (compounds of formula (I)) can the also be purified further
The compounds of formula (I) are new.
Therefore, the present invention also relates to the compound of formula (I) ,
Figure imgf000015_0001
wherein R1 is a C1 – C6-alkyl moiety, and the * marks the chiral centre. Therefore, the present invention also relates to the compound of formula (I) ,
Figure imgf000015_0002
wherein R1 is a C1 – C4-alkyl moiety, and the * marks the chiral centre. Therefore, the present invention also relates to the compound of formula (I) ,
Figure imgf000015_0003
wherein R1 is a C1- C2-alkyl moiety, and the * marks the chiral centre. Furthermore, the present invention also relates to the compounds of formula (Ia) ,
Figure imgf000016_0001
wherein R1 is a C1 – C6-alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ia) ,
Figure imgf000016_0002
wherein R1 is a C1 – C4-alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ia) ,
Figure imgf000016_0003
wherein R1 is a C1 – C2-alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ib) ,
Figure imgf000017_0003
wherein R1 is a C1 – C6-alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ib) ,
Figure imgf000017_0001
wherein R1 is a C1 – C4-alkyl moiety. Furthermore, the present invention also relates to the compounds of formula (Ib) ,
Figure imgf000017_0002
wherein R1 is a C1 – C2-alkyl moiety. 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, 1.47 g (11.18 mmol) (R)-3-hydroxy-4,4- dimethyldihydrofuran-2(3H)-one and 4.20 g (47.8 mmol) crotonyl acid were dissolved in 40 ml toluene in the presence of 94 ^l (15 mol%, 1.696 mmol) H2SO4 (96.7%).The mixture was stirred at 400 rpm and heated at 383 K (internal temperature) for 18 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 99.4 % purity (Area-%). Yield 2.02 g (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl (E)-but-2-enoate, 91 % based on (R)- 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one. Example 2 In a 55-ml flask equipped with a magnetic-stirrer, 2.02 g (10.13 mmol) (R)-4,4-dimethyl-2- oxotetrahydrofuran-3-yl (E)-but-2-enoate, 400 mg catalyst 5% Pd/Al2O3 and 20 ml 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 3 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 liquid in 98.8 % purity (q-NMR). Yield 1.98 g (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate, 96 % based on (R)-4,4- dimethyl-2-oxotetrahydrofuran-3-yl (E)-but-2-enoate. Example 3 In a 55-ml flask equipped with a magnetic-stirrer, 2.07 g (10.13 mmol) 4,4-dimethyl-2- oxotetrahydrofuran-3-yl (E)-but-2-enoate, 400 mg catalyst 5% Pd/Al2O3 and 20 ml 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 3 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 liquid in 98.6 % purity (q-NMR). Yield 2.06 g (R,S)4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate, 98 % based on 4,4- dimethyl-2-oxotetrahydrofuran-3-yl (E)-but-2-enoate. Example 4 In a 5-ml round bottom flask equipped with a magnetic-stirrer and a reflux condenser, 500 mg (2.415 mmol) (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate (from Example 2) and 191 ml (2.462 mmol) 3-aminopropan-1-ol was stirred at 500 rpm at 373 K (oil temperature) for 1 h. The mixture was cooled to room temperature and analyzed without further purification. The crude product was isolated as a viscose colorless liquid in 91 % purity (Area-%). Yield 669 mg 3-hydroxy-4-((3-hydroxypropyl)amino)-2,2-dimethyl-4-oxobutyl butyrate, 92 % based on (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate. Example 5 In a 5-ml round bottom flask equipped with a magnetic-stirrer and a reflux condenser, 500 mg (2.462 mmol) (R,S)4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate (from Example 3) and 191 ml (2.462 mmol) 3-aminopropan-1-ol was stirred at 500 rpm at 373 K (oil temperature) for 1 h. The mixture was cooled to room temperature and analyzed without further purification. The crude product was isolated as a viscose colorless liquid in 93.2% purity (Area-%). Yield 669 mg 3-hydroxy-4-((3-hydroxypropyl)amino)-2,2-dimethyl-4-oxobutyl butyrate, 92 % based on 4,4-dimethyl-2-oxotetrahydrofuran-3-yl butyrate.

Claims

Claims 1. Process for producing a compound of formula (I)
Figure imgf000020_0003
, wherein R is H, or , wherein R1 is a C1 – C6-alkyl moiety (preferably a C1 – C4-alkyl moiety, more preferably a C1- C2-alkyl moiety), and the * marks the chiral centre wherein in a first step (step (i)) a compound of formula (II)
Figure imgf000020_0001
is reacted with a compound of formula (III)
Figure imgf000020_0002
and then in a second step (step (ii)) the reaction product of step (i) is hydrogenated selectively to form the compound of formula (V)
Figure imgf000021_0004
and then in a third step (step (iii) the compound of formula (IV) is reacted with a compound of formula (VI)
Figure imgf000021_0001
wherein R has the same meanings as defined for the compounds of formula (I) to form a compound of formula (I).
2. Process according to claim 1 , wherein the compound of formula (Ila)
Figure imgf000021_0002
is used.
3. Process according to claim 1 , wherein the compound of formula (lib)
Figure imgf000021_0003
is used.
4. Process according to claim 1 , wherein a mixture of the compounds of formula (Ila) and of formula (lib)
Figure imgf000022_0001
is used. Process according to any of the preceding claims, wherein step (i) is carried in at least one inert solvent. Process according to claim 5, wherein the least one solvent is a polar aprotic or apolar aprotic solvent. Process according to any of the preceding claims, wherein the reaction of step (i) is carried in the presence of at least one further acid (next to the compound of formula (III)). Process according to claim 7, wherein the at least one further acid is a strong acid, which has a pKa value below 4. Process according to any of the preceding claims, wherein step (i) is carried out at a temperature of 40 - 150° C. Process according to any of the preceding claims, wherein step (i) the molar ratio of the compound of formula (II) to compound of formula (III) is 1 :1.5. to 1 :10. Process according to any of the preceding claims, wherein step (ii) the hydrogenation is carried out at a pressure of 2 to 10 bar. Process according to any of the preceding claims, wherein step (ii) the hydrogenation of step (ii) is usually carried out in the presence of at least one catalyst.
13. Process according to any of the preceding claims, wherein step (ii) is carried in at least one inert solvent. 14. Process according to any of the preceding claims, wherein step (ii) is carried at a temperature of 25 – 100°C. 15. Process according to any of the preceding claims, wherein step (iii) is carried without any solvents. 16. Compounds of formula (I) ,
Figure imgf000023_0002
wherein R1 is a C1 – C6-alkyl moiety, and the * marks the chiral centre. 17. Compounds of formula (Ia) ,
Figure imgf000023_0001
wherein R1 is a C1 – C2-alkyl moiety. 18. Compounds of formula (Ib) w R
Figure imgf000024_0001
wherein R1 is a C1 – C2-alkyl moiety.
PCT/EP2022/079685 2021-11-02 2022-10-25 Synthesis of pantothenic acid butyrate WO2023078722A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0117260A1 (en) * 1983-02-24 1984-09-05 Tanabe Seiyaku Co., Ltd. 4-Aminobutyric acid derivatives, a process for the preparation thereof and a pharmaceutical composition containing said derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0117260A1 (en) * 1983-02-24 1984-09-05 Tanabe Seiyaku Co., Ltd. 4-Aminobutyric acid derivatives, a process for the preparation thereof and a pharmaceutical composition containing said derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HIRASAWA ET AL: "Conjugate reduction of alpha,beta-unsaturated esters and amides with tributyltin hydride in the presence of magnesium bromide diethyl etherate", TETRAHEDRON, vol. 63, no. 45, 22 August 2007 (2007-08-22), Elsevier Science Publishers, Oxford, GB, pages 10930 - 10938, XP022274963, ISSN: 0040-4020, DOI: 10.1016/j.tet.2007.08.059 *
J. WASER, ET AL.: "Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 128, no. 35, 10 August 2006 (2006-08-10), American Chemical Society, Washington, DC, US, pages 11693 - 11712, XP055349029, ISSN: 0002-7863, DOI: 10.1021/ja062355+ *
J. WASER, ET AL.: "Supporting Information: Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 128, no. 35, 10 August 2006 (2006-08-10), American Chemical Society, Washington, DC, US, pages S1 - S69, XP055910718, ISSN: 0002-7863, DOI: 10.1021/ja062355+ *

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