WO2019185910A2 - Nouvelle utilisation des 2h-chromènes substitués et de leurs dérivés - Google Patents

Nouvelle utilisation des 2h-chromènes substitués et de leurs dérivés Download PDF

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WO2019185910A2
WO2019185910A2 PCT/EP2019/058081 EP2019058081W WO2019185910A2 WO 2019185910 A2 WO2019185910 A2 WO 2019185910A2 EP 2019058081 W EP2019058081 W EP 2019058081W WO 2019185910 A2 WO2019185910 A2 WO 2019185910A2
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Prior art keywords
oil
formula
compound
alkyl
independently
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PCT/EP2019/058081
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English (en)
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WO2019185910A3 (fr
Inventor
Laure CLASADONTE
André DUESTERLOH
Weerasinghe INDRASENA
Thomas Netscher
René Tobias STEMMLER
Chistof WERHLI
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Dsm Ip Assets B.V.
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Publication of WO2019185910A2 publication Critical patent/WO2019185910A2/fr
Publication of WO2019185910A3 publication Critical patent/WO2019185910A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B5/00—Preserving by using additives, e.g. anti-oxidants
    • C11B5/0021—Preserving by using additives, e.g. anti-oxidants containing oxygen
    • C11B5/0035—Phenols; Their halogenated and aminated derivates, their salts, their esters with carboxylic acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B5/00—Preserving by using additives, e.g. anti-oxidants

Definitions

  • the present invention is directed to the use of a compound of formula (I) and/or a compound of formula (II) as antioxidant in oil,
  • the oil contains polyunsaturated fatty acids and/or their esters, and wherein the oil is for human consumption, i.e. wherein the oil is edible, and wherein R 1 and R 2 are independently from each other H or C M 1 -alkyl or (CH 2 ) n — OH with n being an integer from 1 to 6 or R 1 and R 2 together represent a keto group, and
  • R 3 , R 4 , R 5 , and R 6 are independently from each other H or Ci- 6 -alkyl or Ci- 6 -alkoxy, and
  • R 7 is H or Ci- 6 -alkyl.
  • Oils containing polyunsaturated fatty acids and/or their esters are gaining more and more attention, because of their beneficial health effects in humans.
  • the present invention is directed to the use of at least one compound of formula (I) and/or at least one compound of formula (II) as antioxidant in oil, wherein the oil contains polyunsaturated fatty acids and/or their esters, and wherein the oil is for human consumption, i.e. the oil is edible, and wherein R 1 and R 2 are independently from each other H or C M 1 -alkyl or (CH 2 ) n — OH with n being an integer from 1 to 6 or R 1 and R 2 together represent a keto group, and
  • R 3 , R 4 , R 5 , and R 6 are independently from each other H or Ci- 6 -alkyl or Ci- 6 -alkoxy, and
  • R 7 is H or Ci- 6 -alkyl
  • alkyl and“alkoxy” in the context of the present invention encompass linear alkyl and branched alkyl, and linear alkoxy and branched alkoxy, respectively. If one of R 1 and R 2 is an alkyl with more than 4 C-atoms or if one of R 1 and R 2 is a (CH 2 ) n — OH group with more than 4 C-atoms, the other one is preferably H.
  • R 1 and R 2 are independently from each other H or Ci- 4 -alkyl or (CH 2 ) n — OH with n being an integer from 1 to 4, R 3 , R 4 , R 6 and R 7 are independently from each other H or Ci- 4 -alkyl, and R 5 is H or Ci- 4 -alkyl or Ci- 4 -alkoxy.
  • R 1 and R 2 are independently from each other H or Ci- 2 -alkyl or (CH 2 ) n — OH with n being 1 or 2
  • R 3 , R 4 , R 6 and R 7 are independently from each other H or Ci- 2 -alkyl
  • R 5 is H or Ci- 2 -alkyl or Ci- 2 -alkoxy.
  • R 1 and R 2 are independently from each other H or methyl or (CH 2 )— OH
  • R 3 , R 4 , R 6 and R 7 are independently from each other H or methyl or ethyl
  • R 5 is H or methyl or methoxy.
  • R 1 and R 2 are independently from each other H or methyl or (CH 2 )— OH
  • R 3 , R 4 , R 6 and R 7 are independently from each other H or methyl or ethyl
  • R 5 is H or methyl or methoxy.
  • the compounds of the present invention are efficient as antioxidants in PUFA-containing oils for human consumption.
  • PUFA(s) means polyunsaturated fatty acid(s) such as docosahexaenoic acid (“DHA”) and/or eicosapentaenoic acid (“EPA”) and/or docosapentaenoic acid (“DPA”) and/or oleic acid and/or stearidonic acid and/or linoleic acid and/or alpha-linolenic acid (“ALA”) and/or gamma-linolenic acid and/or arachidonic acid (“ARA”) and/or the esters of all of them, whereby the term“esters” encompasses monoglycerides, diglycerides and triglycerides as well as Ci- 6 - alkyl esters such as especially the methyl esters and the ethyl esters, whereby the triglycerides are often dominant.
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DHA, EPA, ALA and stearidonic acid are omega-3 fatty acids, whereas linoleic acid, gamma-linolenic acid and ARA are omega-6 fatty acids.
  • DPA encompasses two isomers, the omega-3 fatty acid clupanodonic acid (7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid) and the omega-6 fatty acid osbond acid (4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid).
  • the polyunsaturated fatty acid is preferably DHA and/or EPA and/or DPA and/or any ester thereof, more preferably the polyunsaturated fatty acid (PUFA) is preferably DHA and/or EPA and/or any ester thereof.
  • - marine oil such as preferably fish oil
  • microbial oil containing polyunsaturated fatty acids and/or their esters
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • PUFA-containing plant oil such as e.g. canola seed oil, linseed/flaxseed oil, hempseed oil, pumpkin seed oil, evening primrose oil, borage seed oil, blackcurrent seed oil, sallow thorn/sea buckthorn oil, chia seed oil, argan oil and walnut oil.
  • Marine oils, microbial oils and algal oils are especially preferred.
  • an edible oil comprising PUFAs and/or their esters and at least one compound of formula (I) and/or at least one compound of formula (II);
  • a method of preserving the shelf life of PUFAs and/or their esters in an edible oil comprising the step of adding at least one compound of formula (I) and/or at least one compound of formula (II) to said edible oil, preferably in an amount of said compound of formula (I) and/or said compound of formula (II) ranging from 10 to 500 ppm, preferably ranging from 30 to 300 ppm, more preferably ranging from 100 to 250 ppm, based on the total amount of the edible oil;
  • a method of limiting the amount of oxidation of PUFAs and/or their esters in an edible oil which is exposed to air comprising adding at least one compound of formula (I) and/or at least one compound of formula (II) to said edible oil, preferably in an amount of said compound of formula (I) and/or said compound of formula (II) ranging from 10 to 500 ppm, preferably ranging from 30 to 300 ppm, more preferably ranging from 100 to 250 ppm, based on the total amount of the edible oil.
  • the compounds of formulae (I) and/or (II) can be used in combination with one or more other antioxidants as described below.
  • the edible PUFA-containing oils of the present invention comprising at least one compound of formula (I) and/or at least one compound of formula (II) additionally comprise ascorbyl palmitate.
  • esters of ascorbic acid such as the esters of ascorbic acid with linear C 12-20 alkanols, preferably the esters of ascorbic acid with linear Ci 4-18 alkanols, may also be used, so that further embodiments of the present invention are directed to edible PUFA-containing oils comprising at least one compound of formula (I) and/or at least one compound of formula (II) that additionally comprise esters of ascorbic acid with linear C 12-20 alkanols, preferably esters of ascorbic acid with linear C 14-18 alkanols, more preferably ascorbyl palmitate.
  • the edible PUFA-containing oils of the present invention comprising at least one compound of formula (I) and/or at least one compound of formula (II) may also comprise additionally alpha-tocopherol and/or gamma-tocopherol, whereby an ester of ascorbic acid with a linear C 12-20 alkanol with the preferences as given above may additionally be present.
  • PUFAs polyunsaturated fatty acids
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DPA docosapentaenoic acid
  • - oil containing high amounts of PUFAs especially containing high amounts of DHA and/or EPA and/or DPA and/or their esters extracted from microbial biomass as e.g., fungi (“fungal oil”) or algae (“algal oil”);
  • PUFA- containing plant oil such as e.g. canola seed oil, linseed/flaxseed oil, hempseed oil, pumpkin seed oil, evening primrose oil, borage seed oil, blackcurrent seed oil, sallow thorn/sea buckthorn oil, chia seed oil, argan oil and walnut oil.
  • DHA does not only encompass the acid but also derivatives thereof such as monoglycerides, diglycerides and triglycerides as well as Ci- 6 -alkyl esters such as the methyl and ethyl esters.
  • EPA monoglycerides
  • DPA dihydroxyacetyl acetate
  • Fish oil and algal oil are commonly used for human consumption. Instead of fish oil and algal oil also the other PUFA-containing oils named above may be used for human consumption, i.e.:
  • biomass such as especially fungal oil
  • the above-mentioned PUFA-containing oils may not only be used as alternative of fish oil and algal oil, but also in addition.
  • suitable marine oils include, but are not limited to, Atlantic fish oil, Pacific fish oil, or Mediterranean fish oil, or any mixture or combination thereof.
  • a suitable fish oil can be, but is not limited to, pollack oil, bonito oil, pilchard oil, tilapia oil, tuna oil, sea bass oil, halibut oil, spearfish oil, barracuda oil, cod oil, menhaden oil, sardine oil, anchovy oil, capelin oil, herring oil, mackerel oil, salmonid oil, tuna oil, and shark oil, including any mixture or combination thereof.
  • Other marine oils suitable for use herein include, but are not limited to, squid oil, cuttle fish oil, octopus oil, krill oil, seal oil, whale oil, and the like, including any mixture or combination thereof.
  • the other PUFA-containing oils such as microbial oil, algal oil, fungal oil and PUFA-containing plant oil.
  • a commercially available example of marine oil is the fish oil “MEG-3” (Bleached 30S TG Fish oil) from DSM Nutritional Products, LLC (US) whose specification and composition is shown in Tables I and II below: Table I
  • the peroxide value is defined as the amount of peroxide oxygen per 1 kilogram of oil. Traditionally this is expressed in units of milliequivalents or meq/kg. Winterization is part of the processing of fish oil, and it is performed to remove solid fat in the oil. The“cold test” is performed to check if any solid fat is present and precipitated in the oil when cooled to 0°C within a specific period of time. In this fish oil (Product Code: FG30TG), any such precipitation is checked for 3 hours at 0°C.
  • Algal oil is an oil containing high amounts of DHA and/or EPA and/or DPA and/or their esters extracted from algae as microbial source/biomass.
  • algal oil is the commercially available“Algal oil containing EPA+DPA” from DSM Nutritional Products, LLC (US) whose composition is shown in the Table III below:
  • a further example of a crude oil containing high amounts of DHA and/or EPA extracted from microbial sources as e.g., algae, is the oil extracted from Algae Schizochytrium Biomass, whose specification is given in the following Table IV.
  • the biomass preferably comprises cells which produce PUFAs hetero- trophically.
  • the cells are preferably selected from algae, fungi, particularly yeasts, bacteria, or protists.
  • the cells are more preferably microbial algae or fungi.
  • Suitable cells of oil-producing yeasts are, in particular, strains of Yarrowia, Candida, Rhodotorula, Rhodosporidium, Cryptococcus, Trichosporon and Lipomyces.
  • Oil produced by a microorganism or obtained from a microbial cell is referred to as“microbial oil”.
  • Oil produced by algae and/or fungi is referred to as an algal and/or a fungal oil, respectively.
  • microorganism refers to organisms such as algae, bacteria, fungi, protist, yeast, and combinations thereof, e.g., unicellular organisms.
  • a microorganism includes but is not limited to, golden algae (e.g., microorganisms of the kingdom Stramenopiles); green algae; diatoms; dinoflagellates (e.g., microorganisms of the order Dinophyceae including members of the genus Crypthecodinium such as, for example,
  • Thraustochytriales yeast ( Ascomycetes or Basidiomycetes); and fungi of the genera Mucor, Mortierella, including but not limited to Mortierella alpina and Mortierella sect, schmuckeri, and Pythium, including but not limited to Pythium insidiosum.
  • microorganisms of the kingdom Stramenopiles may in particular be selected from the following groups of microorganisms:
  • Pelagococcus Ollicola, Aureococcus, Parmales, Diatoms, Xanthophytes, Phaeophytes (brown algae), Eustigmatophytes, Rophidophytes, Synurids, Axodines (including Rhizochromulinales, Pedinellales, Dictyochales), Chrysomeri doles, Sarcinochrysidales, Hydrurales, Hibberdiales, and
  • the microorganisms are from the genus Mortierella, genus Crypthecodinium, genus Thraustochytrium, and mixtures thereof. In a further embodiment, the microorganisms are from Crypthecodinium Cohnii. In a further embodiment, the microorganisms are from Mortierella alpina. In a still further embodiment, the microorganisms are from
  • the microorganisms are selected from Crypthecodinium Cohnii, Mortierella alpina,
  • the microorganisms include, but are not limited to, microorganisms belonging to the genus Mortierella, genus Conidiobolus, genus Pythium, genus Phytophthora, genus Penicillium, genus Cladosporium, genus Mucor, genus Fusarium, genus Aspergillus, genus Rhodotorula, genus Entomophthora, genus Echinosporangium, and genus Saprolegnia.
  • the microorganisms are from microalgae of the order Thraustochytriales, which includes, but is not limited to, the genera Thraustochytrium (species include arudimentale, aureum, benthicola, globosum, kinnei, motivum, multirudimentale, pachydermum, proliferum, roseum, striatum); the genera Schizochytrium (species include aggregatum, limnaceum, mangrovei, minutum, octosporum); the genera Ulkenia (species include amoeboidea, kerguelensis, minuta, profunda, radiate, sailens, sarkariana, schizochytrops, visurgensis, yorkensis); the genera Aurantiacochytrium; the genera Oblongichytrium; the genera Sicyoidochytium; the genera Parientichytrium; the genera Botryochytrium; and combinations thereof.
  • the microorganisms are from the order Thraustochytriales. In yet another embodiment, the microorganisms are from Thraustochytrium. In still a further embodiment, the microorganisms are from Schizochytrium sp.
  • the oil can comprise a marine oil.
  • suitable marine oils are the ones as given above.
  • the biomass according to the invention preferably comprises cells, and preferably consists essentially of such cells, of the taxon
  • Labyrinthulomycetes Labyrinthulea , net slime fungi, slime nets), in particular, those from the family of Thraustochytriaceae .
  • the family of the Thraustochytriaceae includes the genera Althomia, Aplanochytrium, Aurantiochytrium, Botryochytrium, Elnia, Japonochytrium, Oblongichytrium, Parietichytrium, Schizochytrium, Sicyoidochytrium, Thraustochytrium, and Ulkenia.
  • the biomass particularly preferably comprises cells from the genera Aurantiochytrium, Oblongichytrium, Schizochytrium, or Thraustochytrium, more preferably from the genus Schizochytrium.
  • the polyunsaturated fatty acid is preferably DHA and/or EPA and/or their esters as defined above.
  • the cells present in the biomass are preferably distinguished by the fact that they contain at least 20 weight-%, preferably at least 30 weight-%, in particular at least 35 weight-%, of PUFAs, in each case based on cell dry matter.
  • cells in particular a Schizochytrium strain, is employed which produces a significant amount of EPA and DHA, simultaneously, wherein DHA is preferably produced in an amount of at least 20 weight-%, preferably in an amount of at least 30 weight-%, in particular in an amount of 30 to 50 weight-%, and EPA is produced in an amount of at least 5 weight-%, preferably in an amount of at least 10 weight-%, in particular in an amount of 10 to 20 weight-% (in relation to the total amount of lipid as contained in the cells, respectively).
  • PTA-10208 PTA-10209, PTA-10210, or PTA-10211 , PTA-10212, PTA-10213, PTA-10214, PTA-10215.
  • DHA and EPA producing Schizochytrium strains can be obtained by consecutive mutagenesis followed by suitable selection of mutant strains which demonstrate superior EPA and DHA production and a specific EPA:DHA ratio.
  • Any chemical or nonchemical (e.g. ultraviolet (UV) radiation) agent capable of inducing genetic change to the yeast cell can be used as the mutagen.
  • UV radiation ultraviolet
  • These agents can be used alone or in combination with one another, and the chemical agents can be used neat or with a solvent.
  • Methods for producing the biomass in particular, a biomass which comprises cells containing lipids, in particular PUFAs, particularly of the order
  • Thraustochytriales are described in detail in the prior art (see e.g. WO 91 / 07498, WO 94/08467, WO 97/37032, WO 97/36996, WO 01 /54510).
  • the production takes place by cells being cultured in a fermenter in the presence of a carbon source and a nitrogen source, along with a number of additional substances like minerals that allow growth of the
  • biomass densities of more than 100 grams per litre and production rates of more than 0.5 gram of lipid per litre per hour may be attained.
  • the process is preferably carried out in what is known as a fed-batch process, i.e. the carbon and nitrogen sources are fed in incrementally during the
  • the cells are grown until they reach a biomass density of at least 80 or 100 g/l, more preferably at least 120 or 140 g/l, in particular at least 160 or 180 g/l (calculated as dry-matter content).
  • a biomass density of at least 80 or 100 g/l, more preferably at least 120 or 140 g/l, in particular at least 160 or 180 g/l (calculated as dry-matter content).
  • the cells are fermented in a medium with low salinity, in particular, so as to avoid corrosion.
  • This can be achieved by using chlorine- free sodium salts as the sodium source instead of sodium chloride, such as, for example, sodium sulphate, sodium carbonate, sodium hydrogen carbonate or soda ash.
  • chloride is used in the fermentation in amounts of less than 3 g/l, in particular, less than 500 mg/l, especially preferably less than 100 mg/l.
  • PUFA-containing plant oils Plant oils with relatively high amounts of PUFAs, especially with high amounts of DHA and/or EPA such as e.g. , canola seed oil
  • the plant cells may, in particular, be selected from cells of the families Brassi caceae , Elaeagnaceae and Fabaceae.
  • the cells of the family Brassi caceae , Elaeagnaceae and Fabaceae.
  • the cells of the family Brassi caceae , Elaeagnaceae and Fabaceae.
  • Brassicaceae may be selected from the genus Brassica, in particular, from oilseed rape, turnip rape and Indian mustard; the cells of the family
  • Elaeagnaceae may be selected from the genus Elaeagnus, in particular, from the species Oleae europaea ; the cells of the family Fabaceae may be selected from the genus Glycine, in particular, from the species Glycine max.
  • PUFA-containing plant oils containing high amounts of other PUFAs than EPA and/or DHA and/or DPA and/or their esters are linseed/flaxseed oil, hempseed oil, pumpkin seed oil, evening primrose oil, borage seed oil, blackcurrent seed oil, sallow thorn/sea buckthorn oil, chia seed oil, argan oil and walnut oil.
  • Compound of formula (3) is a mixture of compounds of formulae (3a) and (3b).
  • Compound of formula (3) is a mixture of compounds of formulae (3a) and (3b), preferably in the molar ratio of 82:18.
  • the starting material for compound of formula (3), 6-hydroxy-2,2,5,7,8- pentamethylch roman -4-one, may be prepared according to US 2006/193797, Example 1 .
  • the present invention is also directed to a process for the manufacture of a mixture of compounds of formulae (3a) and (3b) comprising the following steps:
  • the methyl-Grignard may be added to the compound of formula (II)
  • step c) is not carried out.
  • the hydroxy group of the compound of formula (I) is a phenolic group which may be protected as ether, acetal or ester, preferably as ether or acetal, according to state-of-the-art methods.
  • phenol protecting groups are methyl ethers; benzyl ethers; silyl ethers, such as e.g. trimethylsilyl, tert-butyldimethylsilyl,
  • the protected phenolic group (“OR” in the compound of formula (II)) may be deprotected easily, i.e. by state-of-the-art methods, to the phenolic group again.
  • a further embodiment of the present invention is a process for the manufacture of compound of formula (5) comprising the following steps:
  • the etherification of compound of formula (1 ) to obtain the compound of formula (5) is either achieved by reaction with an ethyl halide (preferably chloride or bromide) or a carbonate such as diethyl carbonate or dimethyl carbonate.
  • an ethyl halide preferably chloride or bromide
  • a carbonate such as diethyl carbonate or dimethyl carbonate.
  • the Protection Factors of compound of formula (1 ) in fish oil could be improved by the addition of ascorbyl palmitate (“AP”) (see Table 5 in the experimental part) indicating the possibility of combining AP to all the compounds of formulae (1 ) to (7) to improve the oxidative stability of matrices containing high amounts of unsaturated fatty acids such as fish oil.
  • AP ascorbyl palmitate
  • Polymers are combination of complex compounds generated at the end of the oxidation cascade of unsaturated fatty acids and, they indicate the levels of overall oxidation of the matrix.
  • the generation of such polymers in fish oil containing these novel antioxidant compounds of formulae (1 ) to (7) could be reduced considerably when AP was added as a synergistically acting compound (see Table 6 in the experimental part).
  • Examples 1 -6 Syntheses of compounds of formulae (1 ) to (5) and (7)
  • Step 1 acetone, pyrrolidine, acetonitrile
  • Step 2 1 ) MeMgCl. THF, 2) HCl, pTsOH.
  • a procedure by Moody was followed (C. L. Lucas, B. Lygo, A. J. Blake, W. Lewis, C. J. Moody. Regioselectivity of the Claisen Rearrangement in meta-Allyloxy Aryl Ketones: An Experimental and Computational Study, and Application in the Synthesis of (R)-(-)-Pestalotheol D. Chem. Eur. J. 201 1 , 17, 1972-1978).
  • Step 2 A 750 mL 4-necked sulfonation flask equipped with mechanical stirrer, thermometer, 250 mL addition funnel, argon inlet and reflux condenser was inertized with argon and then charged with MeMgCl (3.0 M solution in THF, 128 ml_, 384 mmol, 2.4 mol equiv.) at 20°C. Subsequently, a solution of 6-hydroxy-2,2-dimethylchroman-4-one (33.9 g, 160 mmol) in dry THF (160 ml.) was charged into the addition funnel. The solution was then added over 35 min, keeping the inner temperature below 20° C. The reaction was then heated to reflux for 3 h.
  • MeMgCl 3.0 M solution in THF, 128 ml_, 384 mmol, 2.4 mol equiv.
  • the reaction was cooled to room temperature and diluted with EtOAc (150 ml_). After phase separation, the aqueous phase was extracted with EtOAc (150 ml.) and the combined organic phases were washed with water (2x 100 ml.) and then concentrated in vacuo to furnish 32.8 g of crude product as dark oil. The crude product was then purified by column chromatography. The crude product was diluted with
  • Step 2 PPh 3 AuNTf 2 , DCM Step 1 : A 500 ml. 4-necked flask with magnetic stirrer, thermometer, and argon supply was charged with hydroquinone (22.1 g, 200 mmol, 1.0 mol equiv.) and dissolved in acetonitrile (200 ml_). The solution was cooled to 0- 4°C (ice-bath) and DBU (66.5 g, 440 mmol, 2.2 mol equiv.) and copper(ll) chloride (0.080 g, 0.596 mmol, 0.3 mol%) were added.
  • Step 2 An oven-dried 250 ml. flask with magnetic stirrer, thermometer and argon supply was charged with 4-((2-methylbut-3-yn-2-yl)oxy)phenol (6.4 g, 34.4 mmol, 1 .0 mol equiv.) was dissolved under argon atmosphere in dry DCM (100 nriL) and cooled to 0°C. Ph 3 PAuNTf 2 (0.046 g, 0.062 mmol, 0.2 mol%) was added and the ice bath was removed. After 100 min, another portion Ph 3 PAuNTf 2 (0.25 g, 0.337 mmol, 1.0 mol%) was added.
  • Step 1 Bn-Br, K2CO3, DMF;
  • Step 2 1 ) MeMeCL. THF; 2) aq. HCl, pTsOH;
  • Step 3 BCl 3 , DCM.
  • Step 1 A 3-necked 250 ml. round-bottom flask equipped with thermometer, reflux condenser, argon inlet, magnetic stirring and oil bath was charged with 6-hydroxy-2,2,5,7,8-pentamethylchroman-4-one (14.94 g, 63.8 mmol,
  • the combined organic phases were washed with water (2x 50 ml_), then filtered and concentrated in vacuo, furnishing the crude product as brown solid.
  • the crude product was recrystallized by dissolving in toluene (19 g) at 55°C and slow addition of n-hexane (77 g) at 50-55°C. The solution was allowed to cool to room temperature, upon which crystals formed spontaneously at 20°C. The mixture was cooled to 0°C for 1 h. The crystals were isolated by filtration; the filter cake was washed with the mother liquor and then with little cold n-hexane.
  • Step 2 A 3-necked 250 ml. round-bottom flask equipped with thermometer, reflux condenser, argon inlet, magnetic stirring and oil bath was charged with 6-(benzyloxy)-2,2,5,7,8-pentamethylchroman-4-one (16.9 g, 52.0 mmol, 1.0 mol equiv.) and dissolved in dry THF (104 ml_). The apparatus was then inertized with argon. Subsequently, MeMgCl (3 M in THF, 26 ml_, 78 mmol, 1.5 mol equiv.) was added dropwise within 45 min at 15-20°C. The reaction was then stirred for 4 h at room temperature.
  • HPLC analysis indicated -55 area% starting material and -35 area% addition product. No further conversion was observed; probably due to steric constrains around the ketone moiety.
  • the mixture was cooled to 0°C and HCl (4 M in water, 29 ml_, 1 16 mmol, 2.2 mol equiv.) was added slowly over 20 min at 0-10°C.
  • p- Toluenesulfonic acid (0.33 g, 1.7 mmol, 3 mol%) was added and the mixture was heated to reflux for 30 min. After cooling, water (100 ml.) and Et 2 0 (100 ml.) were added.
  • the aqueous phase was extracted with Et 2 0 (2x 100 ml.) and the combined organic phases were washed with water (2x 50 ml_).
  • the organic phases were concentrated in vacuo (60° C/26 mbar).
  • the residue was re-dissolved in toluene (25 ml.) and EtOH (25 ml.) and concentrated in vacuo (60° C /23 mbar), furnishing the crude product as yellow oil that crystallized on standing (18.24 g,).
  • Step 3 A 3-necked 250 ml. round-bottom flask equipped with thermometer, reflux condenser, argon inlet, magnetic stirring and dry ice bath was charged with 6-(benzyloxy)-2,2,4,5,7,8-hexamethyl-2H-chromene (5.90 g, 18.3 mmol, 82:18 mixture of olefin isomers, 1.0 mol equiv.) and dissolved in dichloromethane (100 ml_). The apparatus was then inertized with argon. Subsequently, the solution was cooled to -40°C and BCI3 (1 M in DCM, 39.5 mmol, 2.1 mol equiv.) was added dropwise over 35 min.
  • the crude product was then purified by column chromatography on silica gel, eluting with hexanes/EtOAc 93:7 (w/w).
  • the product fractions contained varying ratios of product and olefin -isomer. They were combined and concentrated in vacuo, furnishing PM-chromenol and its isomer as yellow oil (3.64 g, 86% yield, mp 66-67°C).
  • Step 1 1 ) NaBH 4 , MeOH, THF; 2) HCl, pTsOH.
  • the reaction was cooled to room temperature and quenched with water (100 ml_).
  • the aqueous phase was extracted with EtOAc (2x 100 ml.) and the combined organic phases were washed with water (2x 50 ml_).
  • the organic phase was concentrated in vacuo, re dissolved in EtOH (100 ml_), filtered and concentrated in vacuo (60°C/20 mbar), furnishing the crude product as yellow oil.
  • the crude product was recrystallized in toluene (9 g) and diluted with n-hexane (18 g). The solution was cooled to 0°C for 1 h and then filtered. The cake was washed with the mother liquor and subsequently with n-hexane (10 ml_). After drying
  • ethyl iodide 11 ml_, 136.8 mmol, 2.7 mol equiv.
  • K 2 C0 3 18.9 g, 136.8 mmol, 2.7 mol equiv.
  • Step 1 Ph 3 PAuNTf 2 , DCM.
  • the starting material 4-(prop-2-yn-1 -yloxy)phenol, was prepared as described in J. C. Jaen, L. D. Wise, T. G. Heffner, T. A. Pugsley, L. T.
  • MNT are mixed natural tocopherols commercially available as e.g.
  • Tocomix 70 IP from AOM (wholesome Aires, Argentina). Tocomix 70 IP comprises d-alpha-tocopherol, d-beta-tocopherols, d-gamma-tocopherols and d-delta-tocopherol, whereby the total amount of tocopherols is at least 70.0 weight-% and the amount of non-alpha tocopherols is at least 56.0 weight-%.
  • the Protection Factors of compound of formula (1 ) as well as MNT in fish oil could be improved by the addition of AP (see Table 5) indicating the possibility of combining AP to all the compounds of formulae (1 ) to (7) to improve the oxidative stability of matrices containing high amounts of unsaturated fatty acids such as fish oil.
  • Polymers are combination of complex compounds generated at the end of the oxidation cascade of unsaturated fatty acids and, they indicate the levels of overall oxidation of the matrix.
  • the generation of such polymers in fish oil containing compound of formula (1 ) could be reduced considerably when AP was added as a synergistic compound (Table 6).
  • Tables 7, 8 and 9 show the PV (peroxide value), p-AV (p-anisidine value) and CD (conjugated dienoic acid in %) of the fish oil samples stabilized with compound of formula (1 ).
  • compound of formula (1 ) was used in fish oil at only 2 mg/g level. Compared to the same level of MNT, compound of formula (1 ) showed much higher PVs than those of MNT (Table 7). MNT had the lowest PV values. There was no considerable variation in p- AV and CD (Tables 8-9) during the storage.
  • Compound of formula (1 ) shows antioxidant properties in fish oil and algal oil at different levels.

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Abstract

La présente invention concerne l'utilisation de 2H-chromènes et de leurs dérivés de formule (I) et/ou de formule (II) où R1 et R2 sont indépendamment l'un de l'autre H ou un alkyle en C1-11 ou (CH2)n— OH, n étant un nombre entier de 1 à 6 ou R1 et R2 représentent ensemble un groupe céto, et où R3, R4, R5, et R6 sont indépendamment les uns des autres H ou un alkyle en C1-6 ou un alcoxy en C1-6, et R7 représente H ou un alkyke en C1-6, à titre d'antioxydants dans des huiles comestibles contenant des AGPI telles que l'huile marine, l'huile microbienne, l'huile fongique, l'huile algale et l'huile végétale contenant des AGPI destinées à la consommation humaine. La présente invention concerne en outre lesdites huiles comestibles contenant des AGPI comprenant au moins un composé de formule (I) et/ou au moins un composé de formule (II). Un procédé de préservation de la durée de conservation des AGPI et/ou de leurs esters dans une huile comestible comprenant l'étape consistant à ajouter au moins un composé de formule (I) et/ou au moins un composé de formule (II) à ladite huile comestible, ainsi qu'un procédé de limitation de la quantité d'oxydation des AGPI et/ou de leurs esters dans une huile comestible qui est exposée à l'air, comprenant l'ajout d'au moins un composé de formule (I) et/ou d'au moins un composé de formule (II) à ladite huile comestible, de préférence en une quantité dudit composé de formule (I) et/ou dudit composé de formule (II) de 10 à 500 ppm, de préférence de 30 à 300 ppm, mieux encore de 100 à 250 ppm, sur la base de la quantité totale de ladite huile comestible sont en outre décrits.
PCT/EP2019/058081 2018-03-29 2019-03-29 Nouvelle utilisation des 2h-chromènes substitués et de leurs dérivés WO2019185910A2 (fr)

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WO2021260087A1 (fr) 2020-06-24 2021-12-30 Fermentalg Procédé de culture de microorganismes pour l'accumulation de lipides
FR3111912A1 (fr) 2020-06-24 2021-12-31 Fermentalg Procédé de culture de microorganismes pour l’accumulation de lipides

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