WO2024038195A1 - Synthèse de propionate de hmo - Google Patents

Synthèse de propionate de hmo Download PDF

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Publication number
WO2024038195A1
WO2024038195A1 PCT/EP2023/072839 EP2023072839W WO2024038195A1 WO 2024038195 A1 WO2024038195 A1 WO 2024038195A1 EP 2023072839 W EP2023072839 W EP 2023072839W WO 2024038195 A1 WO2024038195 A1 WO 2024038195A1
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WIPO (PCT)
Prior art keywords
formula
compound
substituents
process according
present
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PCT/EP2023/072839
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English (en)
Inventor
Casper DE BOER
Werner Bonrath
Ronald Gebhard
Alissa GOETZINGER
Bettina Wuestenberg
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Dsm Ip Assets B.V.
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Publication of WO2024038195A1 publication Critical patent/WO2024038195A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • Propionate compounds are very useful compounds, either as such or as intermediates in organic synthesis, or nutrition and food preservation. It is known that propionate is a major microbial fermentation metabolite in the human gut with putative health effects that extend beyond the gut epithelium. Propionate is thought to lower lipogenesis, serum cholesterol levels, and carcinogenesis in other tissues. Steering microbial propionate production through diet could therefore be a potent strategy to increase health effects from microbial carbohydrate fermentation.
  • the present review first discusses the two main propionate-production pathways and provides an extended gene-based list of microorganisms with the potential to produce propionate. Second, it evaluates the promising potential of arabinoxylan, polydextrose, and L-rhamnose to act as substrates to increase microbial propionate. Furthermore, given the complexity of the gut microbiota, propionate production is approached from a microbial-ecological perspective that includes interaction processes such as cross- feeding mechanisms. Finally, it introduces the development of functional gene-based analytical tools to detect and characterize propionate-producing microorganisms in a complex community.
  • Propionate is thought to lower lipogenesis, serum cholesterol levels, and carcinogenesis in other tissues. Steering microbial propionate production through diet could therefore be a potent strategy to increase health effects from microbial carbohydrate fermentation. Due to the importance of propionates, the goal of the present invention was to provide a way to produce propionate compounds having all advantages in a good yield. Surprisingly, it was found that specific propionate compounds as defined by the formula below can be obtained in good yields and selectivities by a new and easy process.
  • the present invention relates to a process (P) for producing a compound of formula (I) , wherein R, R 1 , R 2, R 3 , R 4 R 5 , R 6 R 7 , R 8 and R 9 are either H or , with the proviso that less than 5 substituents are H, characterised in that a compound of formula (II) is reacted with a compound of formula (III) wherein X is a halogen atom, -OH or the following moiety (* marks the bond to the CO group).
  • the process according to the present invention relates to a process for producing a compound of formula (I) , wherein R, R1, R2, R3, R4 R5, R6 R7, R8 and R9 are either with the proviso that less than 4 substituents are H. (more preferably less than 3 substituents are H, even more preferably less than 2 substituents are H, more preferably none of the substituents are H). Therefore, the present invention relates to a process (P1), which is process (P), wherein the compound of formula (I) less than 4 substituents are H. Therefore, the present invention relates to a process (P1’), which is process (P), wherein the compound of formula (I) less than 3 substituents are H.
  • the present invention relates to a process (P1’’), which is process (P), wherein the compound of formula (I) less than 2 substituents are H. Therefore, the present invention relates to a process (P1’’’), which is process (P), wherein the compound of formula (I) none of the substituents are H. It is clear that it is possible to get mixtures of compounds of formula (I), which have a different substitution pattern. In the following the process according to the present invention is discussed and described in more detail. As stated above the starting material is the compound of formula (II) . This compound is known as 2'-Fucosyllactose (2’-FL). 2’-FL is a human milk oligosaccharide (HMO).
  • 2’-FL is a human milk oligosaccharide (HMO).
  • HMOs Human milk oligosaccharides
  • 2’-FL has a positive influence on short-chain fatty acids in the gut. 2’-FL can be isolated or synthesized. Alternatively, it is also available commercially from a variety of suppliers.
  • the present invention relates to a process (P2), which is the process (P), (P1), (P1’), (P1’’) or (P1’’), wherein the 2’-FL is reacted with a compound of formula (III) wherein X is a halogen atom, -OH or the following moiety (* marks the bond to the CO group).
  • the present invention relates to a process (P2’), which is the process (P), (P1), (P1’), (P1’’) or (P1’’), wherein the 2’-FL is reacted with a compound of formula (III) wherein X is a -Cl, -OH or the following moiety (* marks the bond to the CO group). Therefore, the present invention relates to a process (P2’’), which is the process (P), (P1), (P1’), (P1’’) or (P1’’’), wherein the 2’-FL is reacted with a compound of formula (IIIa) .
  • the process according to the present invention is carried out in the presence of at least one polar, basic, inert solvent.
  • a solvent is usually chosen from the group consisting of pyridines, such as pyridine, substituted pyridines such as dimethyl aminopyridines, or methyl pyridines, or trialkylamines such as triethylamine, diisopropylethylamine, or tributylamine.
  • the present invention relates to a process (P3), which is the process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’) or (P2’’), wherein the reaction is carried out in the presence of at least one polar, basic, inert solvent. Therefore, the present invention relates to a process (P3’), which is the process (P3), wherein the at least one polar, basic, inert solvent is chosen from the group consisting of pyridines, substituted pyridines and trialkylamines.
  • the present invention relates to a process (P3’’), which is the process (P3), wherein the at least one polar, basic, inert solvent is chosen from the group consisting of pyridines, dimethyl aminopyridines, methyl pyridines, triethylamine, diisopropylethylamine and tributylamine.
  • the solvent is used in molar excess in view of the compound of formula (II).
  • the amount of the solvent is not critical for the process according to the present invention.
  • the present invention relates to a process (P4), which is the process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’) or (P3’’), wherein the solvent is used in molar excess in view of the compound of formula (II).
  • the compound of formula (III) needs to be added in such an amount that all (or at least 6 positions) of the compound of formula (II) are propionated.
  • the compound of formula (III) is used in a molar ratio regarding compound of formula (II) of 6:1 to 100 (preferably 10:1 to 100:1).
  • the present invention relates to a process (P5), which is the process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’), (P3’’) or (P4), wherein the compound of formula (III) is used in a molar ratio in regard to compound of formula (II) of 6:1 to 100.
  • the present invention relates to a process (P5’), which is the process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’), (P3’’) or (P4), wherein the compound of formula (III) is used in a molar ratio in regard to compound of formula (II) of 10:1 to 100:1.
  • the process of the present invention can be carried out in a mixture of organic and inorganic bases.
  • Organic bases are i.e., pyridines, such as pyridine; substituted pyridines such as dimethyl aminopyridines, or methyl pyridines; or trialkylamines such as triethylamine, diisopropylethylamine, or tributylamine.
  • Inorganic bases are i.e., carbonates, such as potassium or sodium carbonate and the corresponding hydrogen carbonates.
  • the present invention relates to a process (P6), which is process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’), (P3’’), (P4), (P5) or (P5’), wherein the reaction is carried in a mixture of at least one organic base and at least one inorganic base. Therefore, the present invention relates to a process (P6’), which is process (P6), wherein the at least one organic base is chosen from the group consisting of pyridines, substituted pyridines and trialkylamines.
  • the present invention relates to a process (P6’’), which is process (P6), wherein the at least one organic base is chosen from the group consisting of pyridine, dimethyl aminopyridines, methyl pyridines, triethylamine, diisopropylethylamine and tributylamine. Therefore, the present invention relates to a process (P6’’’), which is process (P6), wherein the at least one inorganic base is chosen from the group consisting of carbonates and the corresponding hydrogen carbonates. Therefore, the present invention relates to a process (P6’’’’), which is process (P6), wherein the at least one inorganic base is chosen from potassium carbonate, sodium carbonate and the corresponding hydrogen carbonates.
  • the reaction is carried out at a temperature of between 15–50° C (more preferably at a temperature of between 20–30° C). Therefore, the present invention relates to a process (P7), which is process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’), (P3’’), (P4), (P5), (P5’), (P6), (P6’), (P6’’), (P6’’’) or (P6’’’’), wherein the reaction is carried out at a temperature of 15 – 50° C.
  • the present invention relates to a process (P7’), which is process (P), (P1), (P1’), (P1’’), (P1’’’), (P2), (P2’), (P2’’), (P3), (P3’), (P3’), (P4), (P5), (P5’), (P6), (P6’), (P6’’), (P6’’’) or (P6’’’’), wherein the reaction is carried out at a temperature of 20–30° C.
  • the isolation of the reaction compound (compound of formula (I)) is carried by using commonly known methods.
  • the reaction product of step (i) can be purified. This is also done by commonly known and used methods.
  • the compounds of formula (I) are new. Therefore, the present invention relates to compounds of formula (I) , wherein R, R 1 , R 2, R 3 , R 4 R 5 , R 6 R 7 , R 8 and R 9 are either with the proviso that less than 4 substituents are H. (more preferably less than 3 substituents are H, even more less than 2 substituents are H, more preferably wherein none of the substituents are H).
  • 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.
  • Example 1 Synthesis of 2'-FL perpropionate 2'-Fucosyllactose (1.14 g, 2.33 mmol) was placed in a 100 mL 3-necked round-bottom flask under an argon atmosphere. A mixture of pyridine (20.7 ml, 256 mmol) and propionic acid anhydride (18.0 ml, 107 mmol) was added in one portion. The resulting white turbid mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted in dichloromethane and extracted several times with a total 125 of sat. aq.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de propionate de 2'-fucosyllactose spécifiques, une synthèse nouvelle et améliorée de propionates de 2'-fucosyllactose spécifiques ainsi que leur utilisation. Les composés propionate sont des composés très utiles.
PCT/EP2023/072839 2022-08-19 2023-08-18 Synthèse de propionate de hmo WO2024038195A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22191269.4 2022-08-19
EP22191269 2022-08-19

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WO2024038195A1 true WO2024038195A1 (fr) 2024-02-22

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364957A1 (fr) * 2001-02-26 2003-11-26 Kissei Pharmaceutical Co., Ltd. Derives de glycopyranosyloxypyrazole et utilisation medicinale de ceux-ci
WO2006120697A2 (fr) * 2005-02-22 2006-11-16 Pharmed Medicare Private Limited Synthese stereoselective de sucrose-6-ester mediee par de l'etain
WO2013004669A1 (fr) * 2011-07-01 2013-01-10 National University Of Ireland, Galway Oligosaccharides multivalents
WO2016038192A1 (fr) * 2014-09-12 2016-03-17 Basf Se Procédé de préparation de 2'-o-fucosyllactose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1364957A1 (fr) * 2001-02-26 2003-11-26 Kissei Pharmaceutical Co., Ltd. Derives de glycopyranosyloxypyrazole et utilisation medicinale de ceux-ci
WO2006120697A2 (fr) * 2005-02-22 2006-11-16 Pharmed Medicare Private Limited Synthese stereoselective de sucrose-6-ester mediee par de l'etain
WO2013004669A1 (fr) * 2011-07-01 2013-01-10 National University Of Ireland, Galway Oligosaccharides multivalents
WO2016038192A1 (fr) * 2014-09-12 2016-03-17 Basf Se Procédé de préparation de 2'-o-fucosyllactose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Greene's Protective Groups in Organic Synthesis, Fourth Edition", 1 January 2007, article P. GREENE M. WUTS ET AL: "PROTECTION FOR THE HYDROXYL GROUP, INCLUDING 1,2-AND 1,3-DIOLS", pages: 16 - 366, XP055406157 *
CLANEY L PEREIRA ET AL: "Synthesis of Human Milk Oligosaccharides: 2'- and 3'-Fucosyllactose", HETEROCYCLES, JAPAN INSTITUTE OF HETEROCYCLIC CHEMISTRY, JP, vol. 84, no. 1, 1 January 2012 (2012-01-01), pages 637 - 655, XP008174628, ISSN: 0385-5414, [retrieved on 20110726], DOI: 10.3987/COM-11-S(P)37 *

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