Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
  • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/02—Preparation of carboxylic acid esters by interreacting ester groups, i.e. transesterification
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/52—Stabilizers
  • A61K2800/522—Antioxidants; Radical scavengers

Definitions

• the synthesis of the compounds is carried out by reaction of synthetic, natural hydroxytyrosol, or as an intermediate compound for the reduction of 3,4-dihydroxyphenylacetic acid or any of its derived esters, or of the natural hydroxytyrosol, oleuropein or aglucones compounds.
• Oleuropein found in olive oil, alpechin, olive pomace or olive leaves
• an acylating agent that is a compound that contains at least one acyl group of the remainder R, where R is H, an alkyl radical with linear, branched or cyclic carbon chain structure, substituted or not, of 1 to 31 carbon atoms, or an alkenyl radical with linear, branched or cyclic carbon chain structure, substituted or not, of up to 31 carbon atoms or a aryl group.
• the esters prepared by the process of the invention can be used as an additive in food and cosmetic products, as well as in pharmaceutical preparations.
• antioxidant additives are used in the preparation of food products [RD 145/1997, BOE of 3/22/97, p. 9378 et seq.]
• cosmetics ["Inventory of Cosmetic Ingredients", Publications Center of the Ministry of Health and Consumer Affairs, Madrid, 1996], both natural and synthetic, depending on the nature, more or less lipid, of the product that It is intended to protect against oxidation.
• polyphenolic compounds stand out for their high activity, especially ortho and paracatecho. Hydroxytyrosol (II) is one such o-catechol, and is found in various natural sources, its presence in the olive tree being especially important [A. VAZQUEZ RONCERO, Rev. Fr.
• Hydroxytyrosol has a much greater protective capacity against oxidation than the antioxidant additives normally used in the preservation of fatty food products: tocopherols (naturally occurring antioxidants) and butyl hydroxytoluol (BHT, synthetic antioxidant) [M. SERVILI et al, Rev. Ital. Sostanze Grasse, 73 (1996) 55].
• BHT butyl hydroxytoluol
• the object of the present invention is a process for the preparation of hydroxytyrosol esters of the general formula:
• the procedure is a regioselective esterification reaction consisting of the following stages: a) contact between any of the following compounds
• the acylating agent is a compound that contains at least one acyl group of the R moiety.
• the radical R of the general formula may be H, an alkyl radical, an alkenyl radical or an aryl group.
• the alkyl radical may be any radical with a linear, branched or cyclic carbon chain structure, substituted or not, of up to 31 carbon atoms inclusive.
• the alkenyl radical may be any radical with a linear, branched or chain: carbon chain structure, substituted or not, of up to 31 carbon atoms inclusive, having one or more degrees of unsaturation at any position in the chain.
• the aryl radical is a phenyl group or a derivative thereof substituted.
• the reaction is regioselective at least 95%.
• the reaction is carried out in the presence or absence of an inert solvent and an acidic or enzymatic catalyst.
• the solvent is selected from some of the following: esters, ethers or halogenated hydrocarbons.
• the catalyst can be a mineral acid, phosphoric acid, an organylsulfonic acid or a lipase.
• the reaction proceeds at room temperature for a period of time between 30 minutes and 24 hours.
• the process object of the invention may include, after the contact step, the isolation and purification of the hydroxytyrosol esters obtained.
• hydroxytyrosol esters obtainable by the above procedure in which the acyl moiety is constituted by a chain that may contain:
• Hydroxytyrosol esters whether or not obtained by the process of the invention, can be used as additives in food formulations, in cosmetic products and in pharmaceutical preparations.
• reaction products obtained, without subsequent isolation of the esters can be used as additives in the mentioned applications.
• esters may be added alone or together with other natural antioxidants of the orthodiphenolic or diterpenic type, in an amount such that their total concentration in the apolar phase of the food does not exceed 200 ppm.
• a food formulation containing as an additive hydroxytyrosol esters alone or together with other natural oxidants of orthodiphenolic or diterpenic type in an amount such that their total concentration in the apolar phase of the food does not exceed 200 ppm.
• This invention describes a new process for the preparation of hydroxytyrosol [2- (3,4-dihydroxyphenyl) ethanol] esters of general formula (I)
• R is H, an alkyl radical of between 1 and 31 carbon atoms, whether linear, branched or cyclic, substituted or not, an alkenyl radical of up to 31 linear, branched or cyclic carbon atoms, substituted or not, and with one or more degrees of unsaturation or an aryl group
• Hydroxytyrosol may be of synthetic origin [R. CAPASSO et al, J. Agrie. Food Chem., 47 (1999) 1745; c. BAI et al, J. Agrie. Food Chem., 46 (1998) 3998; R. VERHE et al, Bull. Liaison Groupe Polyphenols, 15 (1992) 237; A. BIANCO et al, Synth. Common. 18 (1988) 1765; p. G.
• hydroxytyrosol can be provided as an intermediate compound for the reduction of 3,4-dihydroxyphenyl acetic acid or any of its derived esters.
• Oleuropein and oleuropein aglucones are of natural origin.
• Both hydroxytyrosol and oleuropein and their aglucones can be contained in the olive, olive oil, olive leaves and in the waste products from the elaboration of olive oil or table olives, mainly, in alpechin , the olive pomace and the washing waters that are obtained in the preparation of Spanish-style green olives.
• alkyl radical of between 1 and 31 carbon atoms means, in the sense used in this description, any radical with a linear, branched or cyclic carbon chain structure, substituted or not, of up to 31 carbon atoms inclusive.
• alkenyl radical of between 1 and 31 carbon atoms means any radical with a linear, branched or cyclic, substituted or unbranched carbon chain structure of up to 31 carbon atoms, even having one or more grades of unsaturation in any position of the chain.
• aryl means a phenyl group or a benzene derivative substituted with one or more groups of any nature.
• the synthesis of the compounds (I), object of the present invention is carried out by reaction of synthetic hydroxytyrosol (II) (obtained by any of the methods described above) or of the natural products: hydroxytyrosol (II), oleuropein ( III), and aglucones of oleuropein (IV and V) (from any of the sources mentioned above), with an acyl derivative (RCOX), where R has the aforementioned meaning.
• This reaction can be carried out either by heating or at room temperature, and in the presence of an acidic or enzymatic catalyst, according to the following scheme:
• any substance of an acidic nature can be used, preferably: sulfuric acid (H 2 SO 4 ), hydrogen chloride (HCI), phosphoric acid, trifluoroacetic acid (CF 3 COOH), acetic acid (CH 3 COOH), p-toluenesulfonic acid (CH 3 C 6 H 4 SO 3 H), or camphorsulfonic acid (C 10 H 16 OS).
• any enzyme with esterase or lipase activity can be used, preferably: porcine pancreatic lipase
• PPL papain
• horse liver pig, cow, rabbit, or sheep liver esterase
• the reaction can be carried out in the absence or in the presence of solvents that are inert.
• hydroxytyrosol esters obtained by the process of the invention have been subjected to studies to check their antioxidant capacity, having turned out to have the same activity against oxidation as free hydroxytyrosol itself.
• the advantage they have with respect to this is that they are much more soluble in lipid environments (oils, butter, fats, ). Therefore, these compounds of formula (I) are useful for the food and cosmetic industry as antioxidant additives.
• hydroxytyrosol esters have pharmacological effects similar to those observed with hydroxytyrosol, which may be greater due to the greater fat-soluble nature of these molecules.
• the hydroxytyrosol esters obtained by the process of the invention are more soluble in lipids than hydroxytyrosol and have no bitter taste.
• Method C From 3,4-dihydroxyphenylacetic acid A solution of 6 g of 3,4-dihydroxyphenyl acetic acid in 120 mL of dry THF (tetrahydrofuran) is added over a 0.13 M solution of hydride. aluminum and lithium in THF. It is heated at 70 ° C for 4 hours. 300 mL of ethyl acetate and then 90 mL of water are added. The resulting suspension is evaporated in vacuo and the pasty residue is suspended in 200 mL of water, and diluted hydrochloric acid is added until pH 2-3, and the resulting solution is extracted with 7 x 200 mL of ethyl acetate.
• THF tetrahydrofuran
• hydroxytyrosol (II) To a solution of 50 mg of hydroxytyrosol (II) in 0.5 mL of olive oil is added 1 drop of sulfuric acid and the resulting mixture is stirred for 24 hours. The mixture is washed with saturated NaHCO 3 solution, the organic fraction is collected, dried over sodium sulfate and the solvent is evaporated. The mixture of hydroxytyrosol fatty esters (mainly hydroxytyrosol oleate), diluted in the remaining olive oil, can be used without purification.
• hydroxytyrosol (II) To a solution of 50 mg of hydroxytyrosol (II) in 0.5 mL of olive oil is added 1 drop of sulfuric acid and the resulting mixture is stirred for 24 hours. The mixture is washed with saturated NaHCO 3 solution, the organic fraction is collected, dried over sodium sulfate and the solvent is evaporated. The mixture of hydroxytyrosol fatty esters (mainly hydroxytyros
• hydroxytyrosol oleate 83%
• hydroxytyrosol palmitate 11%)
• hydroxytyrosol linoleate 6%

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• 2002
  • 2002-07-03 ES ES200201554A patent/ES2246603B1/es not_active Expired - Fee Related
• 2003
  • 2003-07-02 EP EP03738140A patent/EP1541544A1/en not_active Withdrawn
  • 2003-07-02 AU AU2003244661A patent/AU2003244661A1/en not_active Abandoned
  • 2003-07-02 WO PCT/ES2003/000327 patent/WO2004005237A1/es not_active Ceased
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• 2004
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