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    • 专利摘要:
    Procedure for obtaining dialdehyde secoiridoids. This invention relates to a process for the preparation of dialdehyde secoiridoids, such as oleacein and oleocanthal, by the use of DMSO. This procedure allows to double the yield of the Krapcho reaction with which oleaceine is obtained from oleuropein, present in the olive leaf. Oleacein, a dialdehyde secoiridoid present in virgin olive oil and extra virgin has very interesting biological properties as anti-inflammatory and anti-asthmatic. The Krapcho reaction is used for the first time to the conversion of the monoaldehyde aglycones of oleuropein and ligstrósido, present in phenolic extracts of EVOO, in the corresponding dialdehyde derivatives oleocanth and oleacein, with which a very efficient method of enriching the extracts is achieved phenolic in the dialdehyde secoiridoide, with high added value. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2690412A2
    申请号:ES201700241
    申请日:2017-03-10
    公开日:2018-11-20
    发明作者:José María FERNÁNDEZ-BOLAÑOS GUZMÁN；Inés MAYA CASTILLA；Alejandro GONZÁLEZ BENJUMEA
    申请人:Universidad de Sevilla；
    IPC主号:
    专利说明:

    Title
    Procedure for obtaining dialdehyde secairidoids Object of the invention
    This invention allows doubling the yield of the Krapcho reaction with which oleacein is obtained from oleuropein, present in the olive leaf. Oleacein, a dialdehyde secairidoid present in virgin and extra virgin olive oil, has very interesting biological properties such as anti-inflammatory and anti-asthmatic. The Krapcho reaction has been extended for the first time to the conversion of oleuropein and ligstroside monoaldehyde aglicons, present in phenolic extracts of EVOO, in the corresponding oleocantal dialdehyde derivatives and oleacein, thus achieving a very effective method to enrich the phenolic extracts in dialdehyde dryiridoids, with high added value. A new one is also described
    15 procedure to stabilize and increase the bioavailability of oleacein and oleocantal by acylation and acetalization reactions.
    This invention is part of the production in the areas of Agriculture, Food, Chemistry and Pharmacy.
    The Activity Sector in which the invention can be used corresponds to the Food and Pharmaceutical Industry area. State of the art
    25 The major components of the phenolic fraction of extra virgin olive oils (EVOO) are the oleacein and oleocantal dialdehydes, the olealpein and ligstroside monoaldehyde aglycones, and the corresponding dialdehyde aglyons (1).
    30 It has been described that oleocantal has beneficial properties such as anti-inflammatory (2; 3) and anti-tumor (4; 5) activity. In addition, the oleocantal plays a neuroprotective role in the brain (6; 7), being effective in reducing laamiloid plaques, which contributes to the prevention of Alzheimer's disease (8).
    35 On the other hand, oleacein is a potent antioxidant and a good inhibitor of the enzyme 5-lipoxygenase involved in the biosynthesis of leukotrienes, so that oleacein


    It may be useful in the treatment of asthma and allergic rhinitis (9). It has proven to be an effective drug against diseases related to the degradation of atherosclerotic plaques (10), and has antiproliferative properties (11).
    Recently, a process for transforming oleuropein, the main phenolic compound present in the olive leaf, into oleacein has been described using the Krapcho reaction based on heating in DMSO containing NaCl and water. The published yield for this reaction is 20.5%. It has also been described that
    The oleacein decomposes significantly during chromatographic purification on both silica gel and reverse phase (12).
    The oleocantal can be isolated from EVOO (13) or can be prepared from D-lixose (14). Oleacein can also be synthesized from D-lixose (14).
    References
    (1) Diamantakos P et al. Oleokoronal and oleomissional: new major phenolic ingredients of extra virgin olive oil. Olivae 2015, 122, 23
    (2) Parkinson L & Keast R. Oleocanthal, a phenolic derived from virgin olive oil: a 20 review of the beneficial effects on inflammatory disease. Int J Mol Sci 2014, 15, 12323
    (3) Peyrot Des Gachons C et al. Use of the irritating principal oleocanthal in olive oil, as well as structurally and functionally similar compounds, WO2006122128 A2
    (4) Hodge AM et al. Foods, nutrients and prostate cancer. Cancer Cause Control 2004, 15, 11
    25 (5) LeGendre O et al. (-) - Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization, Mol Cell Oncol 2015, 2, e1006077-1-8
    (6) Heneka et al. Neuroinflammation in Alzheimer’s disease, Lancet Neurol 2015, 14, 388
    (7)  Theoharides TC, Anti-inflammatory compositions for treating neuro-inflammation, 30 US2013115202 A1
    (8) Abuznait et al. Olive oil-derived oleocanthal enhances ȕ-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: In vitro and in vivo studies, ACS Chem Neurosci 2013, 4, 973
    (9) Vougogiannopoulou et al. One-step semisynthesis of oleacein and the 35 determination as a 5-lipoxygenase inhibitor, J Nat Prod 2014, 77, 441


    (10) Czerwinska ME et al. Oleacein for treating or preventing diseases resulting from atherosclerotic plaques, US20160008311
    (eleven) Corona et al. Inhibition of p38 / CREB phosphorylation and COX-2 expression by olive oil polyphenols underlies their anti-proliferative effects. Biochem Biophys Res Commun 2007, 362, 606
    (12) Karkoula et al. Direct measurement of oleocanthal and oleacein levels in olive oil by quantitative 1H NMR. Establishment of a new index for the characterization of extra virgin olive oils. J Agric Food Chem 2012, 60, 11696
    (13) Fogli S et al. Cytotoxic activity of oleocanthal isolated from virgin olive oil on human melanoma cells. Nutr Cancer 2016, 68, 873
    (14) Smith III AB et al. Syntheses of (-) - oleocanthal, a natural NSAID found in extra virgin olive oil, the (-) - deacetoxy-oleuropein aglycone, and related analogues. J Org Chem 2007, 72, 6891. Figures
    Figure 1.- Structures of diacylated oleacein 2 and dehydrated oleuroside aglycone (DOA) diacylated 3.
    Figure 2.- Krapcho demethoxycarbonylation reaction on oleuropein 1 followed by acylation, chromatographic separation and subsequent deacilation.
    Figure 3.- Krapcho demethoxycarbonylation reaction on the monoaldehyde aglycones of oleuropein 6 and ligstroside 7 followed by acylation.
    Figure 4.- Chemoselective monoacetalization reactions on the unconjugated carbonyl of the acylated oleocantal 9 and the diacylated oleacein 2. Description of the invention
    The present invention relates to a process for obtaining oleacein and / or oleocantal dialdehyde secairidoids characterized in that it comprises the treatment of oleuropein and / or ligstroside, respectively, with wet dimethylsulfoxide (DMSO) or hexadeuterated dimethylsulfoxide (DMSO-d6) a temperatures by


    above 140 ° C, using conventional or microwave heating and in the absence of inorganic salt.
    Oleuropein and / or the starting ligstroside can be found mixed with 5 other phenolic compounds
    Then, an improvement of the original process of transforming oleuropein into oleacein by the demethoxycarbonylation reaction of Krapcho in wet DMSO has been carried out. With this invention, based on the absence of halide
    10 alkaline, we improve the previously described process by substantially decreasing the heating time and increasing the yield of oleacein to more than double. In the course of the reaction, a second product, the dehydrated oleuroside aglycone (DOA, Dehydrated Oleuroside Aglycone), of which there is no history can be isolated.
    15 The reaction mixture is acylated in situ, achieving stabilization of both oleacein and DOA and allowing chromatographic purification of both. There is no history of diacylated oleacein; (Figure 1, R = Me).
    Then the process further comprises an acylation step of the oleacein and / or the oleocantal obtained to thus obtain the diacylated oleacein (2) and / or the acylated oleocantal (9),
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    Using the same procedure the conversion of the aglicons is achieved
    oleuropein and ligstroside monoaldehydes in oleacein and oleocantal,
    respectively, by heating in wet DMSO. The transformation can be carried out with the monoaldehyde aglicons separately, or with
    phenolic mixtures, such as mixtures of phenols isolated from oil
    olive. This procedure allows enriching the mixture of phenols in the secairidoides


    oleacein and oleocantal dialdehydes, facilitating chromatographic isolation of both by reducing the number of components of the mixture.
    The acylation of this mixture enriched in phenolic dialdehydes stabilizes both
    5 compounds for the chromatographic purification stage. Both diacylated oleacein 2 and oleocantal 9 can be deacylated using lipase or basic catalyst in alcohol.
    Diacylated dialdehyde derivatives have also been stabilized by their
    Transformation in monoacetal-monoaldehyde derivatives by regioselective acetalization with ethylene glycol on the unconjugated formyl group, keeping the acyl groups on phenolic hydroxyls. In this way, more stable and lipophilic derivatives, and therefore more bioavailable, can be obtained. Subsequent deacylation leads to the 3-ethylidene acetals of oleacein and oleocantal.
    Then, the present invention also comprises the regioselective acetalization with ethylene glycol of the diacylated oleacein (2) and / or the acylated oleocantal (9), thus obtained to obtain compounds 11 and / or 10.
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl, as well as its subsequent deacylation to obtain compound compounds 13 and / or 12.
    In summary, in the present invention the conversion process ofdifferent secairidoid compounds in oleocantal and oleacein by means of a variant of the demethoxycarbonylation of Krapcho in high temperature wet DMSO in the absence of halide (inorganic salt). This reaction can be carried out on isolated oleuropein, on extracts rich in oleuropein, on phenolic fractions


    extracted from extra virgin and extra virgin olive oil, and on isolated monoaldehyde oleuropein and ligstroside aglycones.
    This invention allows enriching phenolic extracts from olive oil5 in oleacein and oleocantal at the expense of their monoaldehyde precursors, and facilitatethe chromatographic separation of said dialdehyde derivatives.
    Krapcho reaction on oleuropein
    Krapcho's reaction on oleuropein 1, or extracts rich in oleuropein, in
    10 wet DMSO or DMSO-d6 at a temperature above 140 ° C in the absence of halide (inorganic salt) leads to oleacein and dehydrated oleuroside aglycone (DOA). Chromatographic purification (silica gel, among other adsorbents) of this mixture only allows DOA to be isolated due to the substantial decomposition of oleacein during the process. The acylation of the mixture allows both compounds to stabilize and
    15 which can also be purified more effectively by chromatographic separation (silica gel, among other adsorbents), which leads to the isolation of the new compounds 2 and 3 (Figure 2). The deacylation of 2 carried out, for example, with lipase or alcohol base (MeOH, among other aliphatic alcohols) leads to oleacein 4 whose spectroscopic data coincide with those of natural oleacein;
    20 Similarly, deacylation of 3 leads to the dehydrated aglycone of the oleuroside (DOA) 5, not previously described. This reaction of Krapcho on the ligstroside leads to oleocantal 8.
    Krapcho reaction on phenolic mixtures from virgin or extra virgin olive oil.
    The reaction of Krapcho with phenolic mixtures from extra virgin or virgin olive oil, containing among other phenolic compounds the monoaldehyde agglons of ligstroside 6 and oleuropein 7, carried out by heating in DMSO 30 or DMSO-d6 at temperatures above 90 ° C leads to the transformation of these monoaldehydes into the corresponding dialdehydes 8 (oleocantal) and 4 (oleacein), whereby the mixture is enriched in said dialdehydes (Figure 3). The chromatographic separation of both dialdehydes allows obtaining pure oleocantal 8 with good performance. The acylation of the mixture of 8 and 4 followed by chromatographic separation allows to obtain acylated oleocantal cigars 9 and diacilated oleacein 2. There is no history of 2, nor of the synthesis of 9 by acylation of oleocantal 8,


    although 9 has been prepared by an alternative route (Smith, III et al. J Org Chem 2007, 72, 6891). The deacylation of 9 to regenerate 8 is carried out, for example, with lipase or alcohol base (MeOH, among other aliphatic alcohols).
    5 The reaction of Krapcho on the isolated lignestroside monoaldehyde aglycone 6, or on the isolated oleuropein monoaldehyde aglycon 7, allows us after removal of the DMSO to obtain oleocantal 8 or oleacein 4 directly, respectively.
    Chemoselective derivatization on unconjugated carbonyl of acylated oleocantal 9 10 or acylated oleacein 2 by acetalization reaction.
    Treatment of acylated derivatives 2 and 9 with ethylene glycol in the presence of a strong acid as a catalyst, for example trifluoroacetic acid, leads to 10 and 11, respectively, acetalized in the unconjugated carbonyl (Figure 4). Deacilation
    15 of these compounds are carried out with the above-mentioned methods that use, for example, lipase or base as a catalyst in the presence of aliphatic alcohol, which allows obtaining monoaceted oleacein 12 and monoacetalized oleocantal 13. Compounds 12 and 13 can also be obtain by acetalization of olecantal 8 and oleacein 4, respectively, with ethylene glycol and acid catalysis. Embodiment of the invention
    Preparation of diacetylated oleacein (2, R = Me) and dehydrated aglycone of acetylated oleuroside (3, R = Me), from oleuropein (1)
    ml) at 150 ° C for 5 h. The reaction mixture is acetylated without removing the solvent using Ac2O (0.4 ml) and a catalytic amount of DMAP (2 mg). One time


    After completion of the reaction (8 h, at room temperature), excess Ac2O is hydrolyzed and concentrated to dryness at low pressure. The residue is purified by column chromatography using as eluent AcOEt-cyclohexane (1: 3 ĺ 1: 1), obtaining acetylated DOA as a colorless syrup (higher RF) and diacetylated oleacein (lower RF) as a colorless syrup.
    Data of acetylated oleacein 2 (R = Me). Yield: 38 mg, 42% RF 0.4 (AcOEtcyclohexane 1: 1),> @ 24 +103. 1H-NMR (300 MHz, CDCl3): G 9.63 (m, 1H, H-3), 9.21 (d,
    Į D
    1H, J = 2.0 Hz, H-1), 7.12 (d, 1H, J = 8.3 Hz, H-7 '), 7.06 (dd, 1H, J = 8.3 Hz, J = 1.9 Hz, H-8') , 7.02 (d, 1H, J = 1.9 Hz, H-4 '), 6.62 (c, 1H, J = 7.1 Hz, H-8), 4.29�4.19 (m, 2H, H1'), 3.63�3.55 ( m, 1H, H-5), 2.97 (ddd, 1H, J = 18.7 Hz, J = 8.5 Hz, J = 1.2 Hz, H-4a), 2.89 (t, 2H, J = 6.7 Hz, H-2 ’), 2.74 (ddd, 1H, J = 18.7 Hz, J = 6.3 Hz, J = 0.9 Hz, H-4b),
    2.68 (dd, 1H, J = 15.8 Hz, J = 8.5 Hz, H-6a), 2.60 (dd, 1H, J = 15.8 Hz, J = 6.5 Hz, H-6b),
    2.28 and 2.27 (2 s, 3H each, 2 Ac), 2.04 (d, 3H, J = 7.1 Hz, H-10). 13C-NMR (125.7 MHz, CDCl3): G 200.6 (C-3), 195.3 (C-1), 172.0 (C-7), 168.5, 168.4 (2 OCOMe), 154.5 (C-8), 143.3 (C -9), 142.1, 140.9 (C5 ', C-6'), 136.8 (C-3 '), 127.1 (C-8'), 124.0 (C-4 '),
    123.5 (C-7 '), 64.5 (C-1'), 46.3 (C-4), 37.0 (C-6), 34.5 (C-2 '), 27.4 (C-5), 20.8 (2 OCOMe) , 15.4 (C-10). HRLSI-MS: calculated for C21H24NaO8 ([M + Na] +): 427.1363, found: 427.1362.
    Data of acetylated dehydrated oleuroside aglycone (DOA) 3 (R = Me). Yield: 12.5 mg, 15%, RF 0.6 (AcOEt-cyclohexane 1: 1), Į D
    24-26. 1H-NMR (500 MHz, CDCl3): G 7.49 (s, 1H, H-3), 7.10 (m, 2H, H-7 ', H-8'), 7.04 (m, 1H, H-4 ') , 6.53 (s, 1H, H-1), 6.14 (dd, 1H, J = 17.6 Hz, J = 11.0 Hz, H-8), 5.30 (d, 1H, J = 17.6 Hz, H10trans), 5.07 (d , 1H, J = 11.0 Hz, H-10cis), 4.23 (m, 2H, J = 6.9 Hz, H-1 '), 3.93 (t, 1H, J = 4.8 Hz, H-5), 3.73 (s, 3H, COOMe), 2.90 (t, 2H, J = 6.9 Hz, H-2 '), 2.63 (dd, 1H, J = 14.4 Hz, J = 4.1 Hz, H-6a), 2.54 (dd, 1H , J = 14.4 Hz, J = 5.5 Hz, H-6b), 2.29 and 2.28 (2 s, 3H each, 2 Ac). 13C-NMR (125.7 MHz, CDCl3): G171.3 (C-7), 168.5, 168.4 (OCOMe), 166.9 (COOMe), 151.5 (C-3), 142.1 (C-5 '), 141.2 (C- 1), 140.8 (C-6 '), 137.1 (C-3'), 127.2 (C-8), 123.9 (C-8 '), 123.4 (C-4'), 123.4 (C-7 '), 117.7 (C-4), 112.7 (C-10), 108.9 (C-9), 64.5 (C-1 '), 51.7 (COOMe), 39.3 (C-6), 34.4 (C-2'), 27.2 (C-5), 20.8 (OCOMe). HRLSI-MS: calculated for C23H24NaO9 ([M + Na] +): 467.1313, found: 467.1310.


    Oleacein (4)
    2 R = Me (12 mg, 0.038 mmol) is dissolved in MeOH (1 ml) and lipase is addedfrom Candida antarctica Novozyme 435 (12 mg). The mixture is heated at 40 5 ° C for 3 h. Once the reaction is finished, it is microfiltered and concentrated to dryness, obtaining the product as an orange syrup. Performance: quant. RF
    0.1 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCl3): G 9.64 (m, 1H, H-3), 9.22 (d, 1H, J = 1.9 Hz, H-1), 6.78 (d, 1H, J = 8.0 Hz, H -7 '), 6.71 (d, 1H, J = 1.9 Hz, H-4'), 6.64 (c, 1H, J = 7.0 Hz, H-8), 6.54 (dd, 1H, J = 8.0 Hz, J = 1.9 Hz, H-8 '), 4.17 (m, 2H, H-1'), 3.69
    10 (m, 1H, H-5), 2.92 (ddd, 1H, J = 19.2 Hz, J = 8.5 Hz, J = 1.2 Hz, H-6a), 2.81�2.62 (m, 5H, H-4, H -2 'and H-6b), 2.05 (d, 3H, J = 7.1 Hz, H-10).
    Dehydrated oleuroside aglycone (DOA, 5)
    15 3 R = Me (32 mg, 0.072 mmol) is dissolved in MeOH (1 ml) andlipase from Candida antarctica Novozyme 435 (32 mg). The mixture is stirred at room temperature for 4 h. Once the reaction is finished, it is microfiltered and concentrated to dryness, obtaining the product as an orange syrup. Performance: quant. RF
    0.45 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCl3): G 7.52 (s, 1H, H-3), 6.78 (d,
    20 1H, J = 8.0 Hz, H-7 '), 6.77 (d, 1H, J = 2.0 Hz, H-4'), 6.61 (dd, 1H, J = 8.0 Hz, J = 2.0 Hz, H-8 '), 6.57 (s, 1H, H-1) 6.15 (dd, 1H, J = 17.6 Hz, J = 11.1 Hz, H-8), 5.35 (d, 1H, J = 17.6 Hz, H-10trans), 5.08 (d, 1H, J = 11.1 Hz, H-10cis), 4.14 (m, 2H, H-1 '), 3.95 (dd, 1H, J = 4.1 Hz, J = 5.5 Hz H-5), 3.77 ( s, 3H, COOMe), 2.80 (t, 2H, J = 6.9 Hz, H-2 '), 2.58 (dd, 1H, J = 14.4 Hz, J = 4.1 Hz, H-6a), 2.54 (dd , 1H, J = 14.4 Hz, J = 5.5 Hz, H-6b).
    Acetylated Oleocantal (9 R = Me)


    8 (100 mg, 0.33 mmol) is dissolved in a mixture of Ac2O / Py 1: 1 (v / v) cooled to 0 ° C. After 15 min it is left under stirring at room temperature one night. Ac2O is hydrolyzed and concentrated to dryness at low pressure and the residue is purified by column chromatography (AcOEt-cyclohexane 1: 2) to obtain a colorless syrup. 5 Performance: quant. 1H-NMR (300 MHz, CDCl3): G 9.63 (m, 1H, H-3), 9.21 (d 1H, J =
    2.0 Hz, H-1), 7.19 (m, 2H, H-4 ', H-8'), 7.01 (m, 2H, H-5 ', H-7'), 6.61 (c, 1H, J = 7.1 Hz, H-8), 4.24 (m, 2H, H-1 '), 3.61 (m, 1H, H-5), 2.97 (ddd, 1H, J = 18.3 Hz, J = 8.5 Hz, J =
    1.1  Hz, H-4a), 2.89 (t, 2H, J = 6.9 Hz, H-2 ’), 2.74 (dd, 1H, J = 18.3 Hz, J = 8.5 Hz, H-4b),
    2.70  (dd, 1H, J = 15.8 Hz, J = 8.4 Hz, H-6a), 2.60 (dd, 1H, J = 15.8 Hz, J = 6.6 Hz, H-6b),
    10 2.29 (s, 3H, Ac), 2.05 (d, 3H, J = 7.1 Hz, H-10). 13C-NMR (75.5 MHz, CDCl3): G 200.5 (C-3), 195.3 (C-1), 172.0 (C-7), 169.7 (COOMe), 154.4 (C-8), 149.5 (C-6 ' ), 143.4 (C-9),
    135.5 (C-3 '), 130.0 (C-4', C-8 '), 121.8 (C-5', C-7 '), 64.9 (C-1'), 46.4 (C-4), 37.0 (C-6),
    34.5 (C-2 ’), 27.4 (C-5), 21.3 (COOMe), 15.3 (C-10). HRESI: calculated for C19H22O6Na ([M + Na] +): 369.1309, found: 369.1309.
    5,6-Di-O-acetylleacein 3-ethylidene acetal (11 R = Me)
    2 R = Me (115 mg, 0.28 mmol) is dissolved in CDCl3 (2 ml) and ethylene glycol (31 μl, 0.56 mmol) and TFA (10.7 μl, 0.14 mmol) are added. The mixture is heated at 50 ° C for 3-20 h, until the starting product is monitored by 1 H-NMR. Finally, the medium is neutralized with NaHCO3 and the product is purified by column chromatography (AcOEt-cyclohexane 1: 2). Yield: 86 mg, 68% RF 0.4 (AcOEt-cyclohexane 1: 1). 1H-NMR (300 MHz, CDCl3): G 9.20 (d, 1H, J = 2.0 Hz, H-1),
    7.09 (d, 1H, J = 8.2 Hz, H-7 ’), 7.06 (dd, 1H, J = 8.2 Hz, J = 1.9 Hz, H-8’), 6.99 (d, 1H, J =
    25 1.9 Hz, H-4 ’), 6.56 (c, 1H, J = 7.1 Hz, H-8), 4.68 (dd, 1H, J = 6.1 Hz, J = 3.6 Hz, H-3),
    4.19 (m, 2H, H-1 ’), 3.89 and 3.76 (2 m, 2 H each, OCH2CH2O), 3.28 (m, 1H, H-5),
    2.85 (t, 2H, J = 6.8 Hz, H-2 '), 2.81 (dd, 1H, J = 15.6 Hz, J = 9.6 Hz, H-6a), 2.60 (dd, 1H, J = 15.6 Hz, J = 5.5 Hz, H-6b), 2.26 and 2.25 (2 s, 3H each, 2 Ac), 2.10 (m, 1H, H-4a),
    1.96 (d, 3H, J = 7.1 Hz, H-10), 1.83 (dt, 1H, J = 14.0 Hz, J = 5.9 Hz, H-4b). 13C-NMR 30 (75.5 MHz, CDCl3): G 195.2 (C-1), 172.4 (C-7), 168.3, 168.2 (OCOMe), 153.0 (C-8),
    144.1 (C-9), 141.9, 140.7 (C-5 ', C-6'), 136.8 (C-3 '), 127.0 (C-8'), 123.8 (C-4 '), 123.3 (C7' ), 103.2 (C-3), 64.8 and 64.7 (OCH2CH2O), 64.3 (C-1 '), 37.5 (C-6), 36.0 (C-4), 34.3 (C


    2 ’), 29.3 (C-5), 20.6 (OCOMe), 14.0 (C-10). HRLSI-MS: calculated for C23H28NaO9 ([M
    + Na] +): 471.1626, found: 471.1613.
    Oleacein 3-ethylidene acetal (13)
    11 (87 mg, 0.19 mmol) is dissolved in MeOH (1 ml), Candida antarctica Novzyme 435 lipase (30 mg) is added and stirred at room temperature for 4 h. The mixture is microfiltered and concentrated to dryness obtaining the product as an orange syrup. Performance: quant. RF 0.3 (AcOEt-cyclohexane 1: 1)
    10 1H-NMR (300 MHz, CDCl3): G 9.21 (d, 1H, J = 1.9 Hz, H-1), 6.76 (d, 1H, J = 8.0 Hz, H7 '), 6.67 (d, 1H, J = 1.5 Hz, H-4 '), 6.57 (c, 1H, J = 7.1 Hz, H-8), 6.50 (dd, 1H, J = 8.0 Hz, J = 1.5 Hz, H-8'), 4.67 ( dd, 1H, J = 6.0 Hz, J = 3.6 Hz, H-3), 6.19 (sa, 2H, OH), 4.11 (m, 2H, H-1 '), 3.89 and 3.75 (2 m, 2 H each one, OCH2CH2O), 3.31 (m, 1H, H-5), 2.77 (dd, 1H, J = 15.5 Hz, J = 9.4 Hz, H-6a), 2.68 (t, 2H, J = 6.8 Hz, H- 2 '), 2.59 (dd, 1H, J = 15.5
    15 Hz, J = 5.6 Hz, H-6b), 2.12 (m, 1H, H-4a), 1.97 (d, 3H, J = 7.1 Hz, H-10), 1.83 (dt, 1H, J = 14.1 Hz , J = 5.8 Hz, H-4b). 13C-NMR (75.5 MHz, CDCl3): G 195.7 (C-1), 172.6 (C-7),
    153.8 (C-8), 144.4 (C-5 '), 144.1 (C-9), 143.3 (C-6'), 129.9 (C-3 '), 120.7 (C-8'), 116.4 (C- 4 '), 116.0 (C-7'), 103.3 (C-3), 65.3 (C-1 '), 64.9, 64.8 (OCH2CH2O), 37.7 (C-6), 36.1 (C-4), 34.4 ( C-2 '), 29.3 (C-5), 15.1 (C-10). HRLSI-MS: calculated for C19H24NaO7 ([M
    20 + Na] +): 387.1414, found 387.1401.
    Oleocantal 3-ethylidene acetal (12)
    8 (33 mg, 0.11 mmol) is dissolved in CDCl3 (1ml) and ethylene glycol (0.22 mmol) and TFA (0.054 mmol) are added. The mixture is heated to 50 ° C and monitored by 1 H-NMR until complete conversion. The mixture is neutralized with NaHCO3 and concentrated to


    dryness. The residue is purified by column chromatography (AcOEtcyclohexane 1: 2) to obtain a colorless syrup. Yield: 31 mg, 84%. 1H-NMR (300 MHz, CDCl3): G 9.23 (d, 1H, J = 2.0 Hz, H-1), 7.02 (m, 2H, H-4 ', H-8'), 6.75 (m, 2H, H-5 ', H-7'), 6.57 (c, 1H, J = 7.1 Hz, H-8), 6.04 (sa, 1H, OH), 4.70 (dd 1H, J = 6.0 Hz, J =
    5 3.7 Hz, H-3), 4.16 (m, 2H, H-1 '), 3.86, 3.78 (2 m, 2H each, OCH2CH2O), 3.31 (m, 1H, H-5), 2.79 (t, 2H, J = 7.0 Hz, H-2 '), 2.78 (dd, 1H, J = 15.7 Hz, J = 9.3 Hz, H-6a), 2.62 (dd, 1H, J = 15.7 Hz, J = 5.8 Hz, H-6b), 2.14 (ddd, 1H, J = 14.0 Hz, J = 9.3 Hz, J = 3.7 Hz, H-4a), 1.98 (d, 3H, J = 7.1 Hz, H-10), 1.84 (dt , 1H, J = 14.0 Hz, J = 6.0 Hz, H-4b). 13C-NMR (75.5 MHz, CDCl3): G 195.3 (C-1), 172.0 (C-7), 154.8 (C-6 ’), 153.5 C-8), 143.2 (C 10 9), 130.1 (C-4 ', C-8'), 129.6 (C-3 '), 115.5 (C-5', C-7 '), 103.4 (C-3), 65.3 (C-1 '), 64.8,
    64.9 (OCH2CH2O), 37.7 (C-6), 36.1 (C-4), 34.3 (C-2 ’), 29.3 (C-5), 15.1 (C-10). HRCI: calculated for C19H24NaO6 ([M + Na] +): 371.1465, found: 371.1456.
    4-O-Acetylleocantal 3-ethylidene acetal (10 R = Me)
    12 (31 mg, 0.108 mmol) is dissolved in CH2Cl2 (1 mL) and Ac2O (12.2 µl, 0.16 mmol) and a catalytic amount of DMAP are added. It is stirred at room temperature overnight and hydrolyzed with water. The phases are separated and the organic phase is washed with 2x5 ml of water. The organic phase is dried with Na2SO4 and concentrated to dryness. 20 Performance: quant. 1H-NMR (300 MHz, CDCl3): G 9.23 (d, 1H, J = 2.0 Hz, H-1), 7.17 (m, 2H, H-4 ', H-8'), 7.00 (m, 2H, H-5 ', H-7'), 6.55 (c, 1H, J = 7.1 Hz, H-8), 4.69 (dd, 1H, J = 6.1 Hz, J = 3.6 Hz, H-3), 4.17 ( m, 2H, H-1 '), 3.85, 3.77 (2 m, 2H each, OCH2CH2O), 3.30 (m, 1H, H-5), 2.86 (t, 2H, J = 6.9 Hz, H-2' ), 2.80 (dd, 1H, J = 15.7 Hz, J = 9.5 Hz, H-6a), 2.62 (dd, 1H, J = 15.7 Hz, J = 5.6 Hz, H-6b), 2.28 (s, 3H, Ac), 2.14 25 (ddd, 1H, J = 13.9 Hz, J = 9.2 Hz, J = 3.6 Hz, H-4a), 1.97 (d, 3H, J = 7.0 Hz, H-10), 1.84 (dt, 1H, J = 14.0 Hz, J = 5.9 Hz, H-4b). 13C-NMR (75.5 MHz, CDCl3): G 195.2 (C-1),
    172.5 (C-7), 169.7 (OCOMe), 153.0 (C-8), 149.5 C-6 '), 144.2 (C-9), 135.6 (C-3'), 130.0 (C-4 ', C- 8 '), 128.7 (C-5', C-7 '), 103.4 (C-1), 64.9 (OCH2CH2O), 64.8 (C-1'), 64.7 (OCH2CH2O), 37.6 (C-6), 36.1 (C-4), 34.5 (C-2 '), 29.4 (OCOMe), 21.2 (C-5), 15.0 (C
    30 10). HRESI: calculated for C23H28NaO9 ([M + Na] +): 471.1626, found: 471.1613.

    权利要求:
    Claims (8)
    [1]
     Claims
    1. Procedure for obtaining oleacein and / or oleocantal dialdehyde secairidoids characterized in that it comprises the treatment of oleuropein and / or
    5 ligstroside, respectively, with wet dimethylsulfoxide (DMSO) or hexadeuterated dimethylsulfoxide (DMSO-d6) at temperatures above 140 ° C, using conventional or microwave heating and in the absence of inorganic salt.
    [2]
    2. The method according to claim 1 wherein the oleuropein and / or the starting lystroside are mixed with other phenolic compounds.
    [3]
    3. Method according to any of claims 1-2 characterized in that it further comprises an acylation step of the oleacein and / or the oleocantal obtained in order to obtain the diacylated oleacein (2) and / or the acylated oleocantal (9),
    where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    [4]
    4. Method according to claim 3 characterized in that it comprises the regioselective acetalization with ethylene glycol of the diacylated oleacein (2) and / or the acylated oleocantal (9), thus obtained to obtain compounds 11 and / or 10
    Where R is selected from hydrogen (H), (C1-C22) alkyl, substituted or unsubstituted phenyl.
    [5]
    5. Method according to claim 4 characterized in that it comprises deacylation of compounds 11 and / or 10 to give compounds 13 and / or 12

    [6]
    6. Formula compound
    where R is methyl.
    [7]
    7. Compound of formula
    [8]
    8. Compound of formula

    Figures
    Figure 1
    Figure 2
    Figure 3

    Figure 4
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    同族专利:
    公开号 | 公开日
    EP3594198A2|2020-01-15|
    ES2690412R1|2019-02-08|
    WO2018162769A2|2018-09-13|
    WO2018162769A3|2018-11-08|
    ES2690412B1|2019-11-13|
    EP3594198A4|2021-09-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20130115202A1|2005-08-31|2013-05-09|Theta Biomedical Consulting & Development Co., Inc|Anti-inflammatory compositions for treating neuro-inflammation|
    WO2006122128A2|2005-05-09|2006-11-16|The Trustees Of The University Of Pennsylvania|Use of the irritating principal oleocanthal in olive oil, as well as structurally and functionally similar compounds|
    US20070299129A1|2006-01-05|2007-12-27|Deviris Inc.|Compounds and derivatives for the treatment of medical conditions by modulating hormone-sensitive lipase activity|
    PL227843B1|2012-07-14|2018-01-31|Warszawski Uniwersytet Medyczny|Use of oleacein, especially Ligustrum vulgare L.|ES2769902B2|2018-12-28|2020-12-04|Consejo Superior Investigacion|Use of secoiridoids for the treatment of optic neuritis.|
    EP3838885A1|2019-12-16|2021-06-23|National and Kapodistrian University of Athens|Process for the production of oleocanthal, oleacein and their analogues|
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