WO2024038195A1 - Synthesis of hmo propionate - Google Patents
Synthesis of hmo propionate Download PDFInfo
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- 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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- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- SNFSYLYCDAVZGP-UHFFFAOYSA-N UNPD26986 Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(OC(O)C(O)C2O)CO)OC(CO)C(O)C1O SNFSYLYCDAVZGP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims description 62
- 230000008569 process Effects 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 22
- SNFSYLYCDAVZGP-OLAZETNGSA-N 2'-fucosyllactose Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@H](OC(O)[C@H](O)[C@H]2O)CO)O[C@H](CO)[C@H](O)[C@@H]1O SNFSYLYCDAVZGP-OLAZETNGSA-N 0.000 claims description 13
- 150000003222 pyridines Chemical class 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000012442 inert solvent Substances 0.000 claims description 6
- 125000005270 trialkylamine group Chemical class 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 abstract description 9
- 229940062827 2'-fucosyllactose Drugs 0.000 abstract description 4
- -1 2'-fucosyllactose propionate compounds Chemical class 0.000 abstract description 4
- HWHQUWQCBPAQQH-UHFFFAOYSA-N 2-O-alpha-L-Fucosyl-lactose Natural products OC1C(O)C(O)C(C)OC1OC1C(O)C(O)C(CO)OC1OC(C(O)CO)C(O)C(O)C=O HWHQUWQCBPAQQH-UHFFFAOYSA-N 0.000 abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 101500027295 Homo sapiens Sperm histone HP3 Proteins 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 102400000926 Sperm histone HP3 Human genes 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000000813 microbial effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- GJHFAHVMZHRUFR-UHFFFAOYSA-N 3,4-dimethylpyridin-2-amine Chemical class CC1=CC=NC(N)=C1C GJHFAHVMZHRUFR-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 235000020256 human milk Nutrition 0.000 description 4
- 210000004251 human milk Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 230000008821 health effect Effects 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000004132 lipogenesis Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 241001655328 Bifidobacteriales Species 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UGXQOOQUZRUVSS-ZZXKWVIFSA-N [5-[3,5-dihydroxy-2-(1,3,4-trihydroxy-5-oxopentan-2-yl)oxyoxan-4-yl]oxy-3,4-dihydroxyoxolan-2-yl]methyl (e)-3-(4-hydroxyphenyl)prop-2-enoate Chemical compound OC1C(OC(CO)C(O)C(O)C=O)OCC(O)C1OC1C(O)C(O)C(COC(=O)\C=C\C=2C=CC(O)=CC=2)O1 UGXQOOQUZRUVSS-ZZXKWVIFSA-N 0.000 description 1
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical compound C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 description 1
- 229920000617 arabinoxylan Polymers 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 238000009920 food preservation Methods 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 235000013406 prebiotics Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
Classifications
-
- 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)
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Abstract
The present invention relates to new specific 2'-fucosyllactose propionate compounds, to a new and improved synthesis of specific 2'-fucosyllactose propionates as well their use. Propionate compounds are very useful compounds.
Description
Synthesis of HMO Propionate The present invention relates to specific propionate compounds and to a new and improved synthesis of specific propionates as well to their application. 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. The information in this review may be helpful for designing functional food strategies that aim to promote propionate-associated health benefits 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. Therefore, the present invention relates to a process (P) for producing a compound of formula (I)
, wherein R, R1, R2, R3, R4 R5, R6 R7, R8 and R9 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). Preferably, 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.
Therefore, 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). Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that are highly abundant in and unique to human milk. Originally, HMOs were proposed to be prebiotic "bifidus factors," or human milk glycans found to promote growth in Bifidobacterial species of the gut and found uniquely in the stool of breast- fed infants compared to formula fed infants. Furthermore, 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. 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). Preferably
More preferably the compound of formula (IIIa)
is used. 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 (III)
wherein X is a halogen atom, -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 (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)
. Usually and preferably, the process according to the present invention is carried out in the presence of at least one polar, basic, inert solvent. Such 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. Therefore, 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.
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, 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. Therefore, 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. Usually 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). Therefore, 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. Therefore, 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. Furthermore, 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. Therefore, 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. 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 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. Usually and preferably, 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.
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 20–30° C. The isolation of the reaction compound (compound of formula (I)) is carried by using commonly known methods. Furthermore, the reaction product of step (i) can be purified. This is also done by commonly known and used methods. Furthermore, the compounds of formula (I) are new. Therefore, the present invention relates to compounds 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 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.
Examples 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. mL NaHCO3 and once with brine, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. To the residue were added 50 mL of sat. aq. NaHCO3 and the mixture was stirred overnight to hydrolyze excess propionic acid. It was then extracted several times with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated to give 0.790 g of a colorless solid. The crude product was purified by chromatography (SiO2, 40-60 micrometer, heptane/ethyl acetate, detected with ELSD). The product was characterized by 1H-, 13C-NMR spectroscopy, IR-spectroscopy and MS (high resolution). Yield: 29%.
Claims
Claims 1. 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 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). 2. Process according to claim 1, 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). 3. Process according to claim 1, wherein the 2’-FL is reacted with a compound of formula (IIIa)
. 4. Process according to any of the preceding claims, wherein the compound of formula (I) less than 4 substituents are H. 5. Process according to any of the preceding claims, wherein the compound of formula (I) less than 3 substituents are H. 6. Process according to any of the preceding claims, wherein the compound of formula (I) less than 2 substituents are H.
7. Process according to any of the preceding claims, wherein the compound of formula (I) none of the substituents are H. 8. Process according to any of the preceding claims, wherein the reaction is carried out in the presence of at least one polar, basic, inert solvent. 9. Process according to claim 6, wherein the at least one polar, basic, inert solvent is chosen from the group consisting of pyridines, substituted pyridines and trialkylamines. 10. Process according to any of the preceding claims, wherein the compound of formula (III) is used in a molar ratio in regard to compound of formula (II) of 6:1 to 100. 11. Process according to any of the preceding claims, wherein the reaction is carried out at a temperature of 15–50° C. 12. Compounds 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.
13. Compounds of claim 12, wherein less than 3 substituents are H. 14. Compounds of claim 12, wherein less than 2 substituents are H. 15. Compounds of claim 12, wherein none of the substituents are H.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1364957A1 (en) * | 2001-02-26 | 2003-11-26 | Kissei Pharmaceutical Co., Ltd. | Glycopyranosyloxypyrazole derivatives and medicinal use thereof |
| WO2006120697A2 (en) * | 2005-02-22 | 2006-11-16 | Pharmed Medicare Private Limited | Tin mediated regioselective synthesis of sucrose-6-esters |
| WO2013004669A1 (en) * | 2011-07-01 | 2013-01-10 | National University Of Ireland, Galway | Multivalent oligosaccharides |
| WO2016038192A1 (en) * | 2014-09-12 | 2016-03-17 | Basf Se | Method for preparing 2'-o-fucosyllactose |
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- 2023-08-18 WO PCT/EP2023/072839 patent/WO2024038195A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1364957A1 (en) * | 2001-02-26 | 2003-11-26 | Kissei Pharmaceutical Co., Ltd. | Glycopyranosyloxypyrazole derivatives and medicinal use thereof |
| WO2006120697A2 (en) * | 2005-02-22 | 2006-11-16 | Pharmed Medicare Private Limited | Tin mediated regioselective synthesis of sucrose-6-esters |
| WO2013004669A1 (en) * | 2011-07-01 | 2013-01-10 | National University Of Ireland, Galway | Multivalent oligosaccharides |
| WO2016038192A1 (en) * | 2014-09-12 | 2016-03-17 | Basf Se | Method for preparing 2'-o-fucosyllactose |
Non-Patent Citations (2)
| 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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