WO2009151057A1 - Procédé de fabrication d’une substance active antioxydante - Google Patents

Procédé de fabrication d’une substance active antioxydante Download PDF

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Publication number
WO2009151057A1
WO2009151057A1 PCT/JP2009/060547 JP2009060547W WO2009151057A1 WO 2009151057 A1 WO2009151057 A1 WO 2009151057A1 JP 2009060547 W JP2009060547 W JP 2009060547W WO 2009151057 A1 WO2009151057 A1 WO 2009151057A1
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Prior art keywords
general formula
active substance
acid
group
antioxidant active
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PCT/JP2009/060547
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English (en)
Japanese (ja)
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全宏 多田
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国立大学法人東京農工大学
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Priority to JP2010516861A priority Critical patent/JP5464444B2/ja
Publication of WO2009151057A1 publication Critical patent/WO2009151057A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • the present invention relates to a method for producing an antioxidant active substance. More specifically, the present invention relates to a method for producing carnosic acid and its derivatives from trees such as Sawara.
  • Lamiaceae plants such as rosemary, sage, perilla, oregano, basil, thyme, marjoram, peppermint are widely distributed throughout the world, and about 200 genera and 3500 species are known.
  • the antioxidant active substances contained in the Lamiaceae plants are roughly classified into four types: phenolic diterpenes, caffeic acid derivatives, flavonoids, and biphenyl derivatives.
  • rosemary has long been known as a spice for meat dishes and a folk medicine, and it is widely known that it contains a strong antioxidant active component typified by carnosic acid, carnosol, and rosmanol ( Non-patent document 1).
  • the above-mentioned antioxidant active substances contained in such rosemary have antibacterial activity, cranial nerve cell death prevention effect, cerebral blood treatment / prevention effect, Alzheimer's disease prevention effect, fat absorption prevention effect, anti-inflammatory effect, diabetes
  • Various activities such as blood glucose lowering effect and whitening effect of patients have been reported, and their use as food additives, supplements, medicines, etc. are being studied (Patent Document 1, Non-Patent Document 2 to Non-Patent Document 4). .
  • a neurite elongation agent containing at least one plant-derived extract selected from the group consisting of rosemary and sage as an active ingredient is disclosed (Patent Document 2). It is disclosed that the carnosic acid which is an example of the said extract is obtained by extracting predetermined parts, such as rosemary, with alcohol. However, carnosic acid separated from an extract of rosemary obtained by alcohol treatment or the like with respect to 5,000 grams of rosemary whole plant is only 1.5 grams, and there is a problem that the production efficiency is not sufficient.
  • rosemary leaves are treated with a lower alkyl alcohol aqueous solution in the presence of a water-soluble acid, and carnosic acid is optionally extracted.
  • a method including purification is disclosed (Patent Document 3 and Patent Document 4).
  • rosemary leaves are used as a starting material for carnosic acid.
  • the supply of rosemary leaves varies greatly depending on the production volume and price, and is not sufficient from the viewpoint of a production method that can supply carnosic acid in a large amount at a low cost.
  • Sawara is a special conifer of Japan, and its natural life is distributed a lot in Tochigi, Gunma, and Kamikochi, Nagano Prefecture.
  • the leaves and bark contain a large amount of related compounds such as piciferin acid, which is a raw material for carnosic acid (Non-patent Document 5).
  • Sawara contains a specific substance having activity similar to that of dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA) currently used as synthetic food additives.
  • BHT dibutylhydroxytoluene
  • BHA butylhydroxyanisole
  • the object of the present invention is to extract carnosic acid and derivatives thereof from evergreen broad-leaved trees such as Sawara, which are widely present in Japanese mountains, and extract an antioxidant active substance. May provide a method of manufacturing.
  • the inventors of the present invention obtained strong power by oxidizing the ortho position of phenol of a compound such as piciferin acid, which is an extract thereof, with a specific oxidizing agent. It has been found that carnosic acid and its derivatives, which are antioxidant active ingredients, can be produced, and the present invention has been completed.
  • R 1 is any one of COOR 3 , hydroxymethyl group and aldehyde group, and R 2 and R 3 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • R 2 and R 3 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • R 4 , R 5 and R 6 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an allyl group, a phenyl group, a halogenated phenyl group, a halogen atom.
  • X represents a halogen atom, and n represents 1 or 2).
  • R 1 is any one of COOR 4 , hydroxymethyl group, and aldehyde group
  • R 2 , R 7, and R 4 are each independently a hydrogen atom or a C 1-6 carbon atom.
  • an antioxidant active substance typified by carnosic acid or the like can be produced easily and in large quantities from Sawara with an extremely high yield.
  • an antioxidant active substance such as carnosic acid can be produced by a simple process by using an inexpensive specific oxidation initiator.
  • the term “antioxidant active substance” refers to a compound having a strong antioxidant activity, such as carnosic acid, carnosol, rosmanol and the like.
  • the term “antioxidant active substance” is not limited to those extracted only from rosemary, but also uses Lamiaceae plants other than rosemary such as sage, perilla, oregano and basil as starting materials, or these starting materials. A composition produced using a combination of these as starting materials.
  • the raw material used in the method for producing an antioxidant active substance of the present invention only needs to contain, in its components, piciferic acid and its derivative, which are raw materials such as carnosic acid, which is the target substance of the production method of the present invention, although it does not restrict
  • the tree of the genus Sawara of the cypress family can be illustrated. Examples of the tree include Sawara, Shinobu hiba, Ogon Shinobu hiba, Himuro and Hiyoku hiba.
  • Sawara is preferable from the viewpoint of production and handling, and these raw materials can be mixed and used.
  • the general formulas for piciferic acid and its derivatives, which are starting materials for the antioxidant substance that is the target substance of the production method of the present invention, are shown below.
  • R 1 is any one of COOR 3 , a hydroxymethyl group, and an aldehyde group. That is, R 1 is a carboxyl group, a carboxylic ester group, a hydroxymethyl group, or an aldehyde group.
  • R 2 and R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. Examples thereof include a group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like.
  • piciferic acid is a diterpene most contained in Sawara, and is a chemically stable, colorless, and odorless crystal.
  • Sawara is an evergreen tree that can be obtained everywhere in Japan and can be obtained very easily. Furthermore, Sawara is a biomass that is readily available and present in large quantities. In the present invention, it is preferable to use the leaves and bark even though a lot of piciferin acid and its derivative compounds are included in the part of Sawara.
  • the method for extracting piciferin acid and the like from raw materials such as Sawara is not particularly limited, and for example, extraction can be performed by the following method. That is, it can be easily extracted by immersing a raw material such as sawara in a solvent or refluxing with a solvent.
  • the solvent that can be used include water, alcohol, alkane, carboxylic acid, ester, and ketone.
  • these solvents can be used alone, or two or more of these solvents can be appropriately mixed and used.
  • Examples of the alcohol include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl 1-propanol, t-butyl alcohol, 1-pentanol, 2-pentanol, and 3-pen.
  • Examples include butanol, 2-methyl 1-butanol, 3-methyl 1-butanol, 2 and 2 dimethyl 1-propanol.
  • Examples of the alkane include pentane, hexane, heptane, octane, nonane and decane.
  • ketones include acetone, methyl ethyl ketone (MEK), and diethyl ketone.
  • MEK methyl ethyl ketone
  • diethyl ketone two or more kinds of the above organic solvents can be adopted and used as a mixed solution.
  • the above solvents from the viewpoint of handling such as safety, it is preferable to use water, alcohol alone or a mixed solvent of water and alcohol. It is particularly preferable to use a mixed solvent of water and ethanol.
  • the extraction time and extraction temperature when performing the above solvent extraction can be appropriately set depending on the type of raw material.
  • the extraction temperature is preferably set to the reflux temperature, and the extraction reaction time can be 10 to 24 hours.
  • the method for producing an antioxidant active substance of the present invention employs a specific peroxide represented by the following general formula in the ortho-position oxidation reaction of phenol in the structural formulas of piciferic acid and derivatives thereof represented by the above chemical formula It has the characteristics. That is, in the present invention, an oxidant represented by the following general formula is used to oxidize the ortho position of phenol in piciferic acid and its derivatives.
  • R 4 , R 5 and R 6 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, an allyl group, a phenyl group, a halogenated group) (Represents either a phenyl group or a halogenated alkyl group.
  • X represents a halogen atom
  • n represents 1 or 2.
  • the methods adopted in the ortho-oxidation reaction of phenols include direct oxidation with selenium oxide, oxidation with benzoyl peroxide, air oxidation, and 2-Iodoxybenzoic acid (hereinafter referred to as “IBX”).
  • IBX 2-Iodoxybenzoic acid
  • examples of the oxidation method may include but are not limited thereto.
  • the use of various oxidizing agents can oxidize piciferin acid derivatives extracted from, for example, Sawara species.
  • benzoyl peroxide (mCBPO) having a halogenated phenyl in which R 4 and R 5 are phenyl halides, and a chloro having a halogenated phenyl and a halogenated alkyl group.
  • Acetylmetachlorobenzoyl peroxide (CAMCBPO) can be used, but is not limited to these oxidizing agents.
  • IBX and diacyl peroxide are used as the oxidizing agent, but the present invention is not limited to this.
  • a benzoic acid derivative represented by the above general formula can also be used as an oxidizing agent.
  • oxidation with IBX often further oxidizes the oxide, producing a complex mixture.
  • the oxide is further oxidized to produce ortho-quinone.
  • ortho-quinone is easily decomposed at anxiety points, so it is converted to catechol by rapid reduction with sodium hydride.
  • mCBPO benzoyl peroxide
  • AMCBPO benzoyl peroxide
  • the above IBX which is an oxidizing agent used in the present invention, can be easily produced from 2-iodobenzoic acid under predetermined conditions.
  • the reaction formula is shown below.
  • the reducing agent used for the reduction reaction of the generated orthoquinone after oxidation with IBX is not particularly limited as long as it is a catalyst having a mild reducing ability that does not reduce the carboxyl group.
  • Examples include lithium aluminum hydride [LiAlH (OR) 3 ], lithium borohydride (LiBH 4 ) sodium borohydride, lithium trialkylborohydride (LiR 3 BH), and dialkylaluminum hydride. These reducing agents may be used alone or in combination.
  • ester group after ortho-position oxidation can also be removed by hydrolysis.
  • a combination of a base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate and a solvent such as water-methanol or water-ethanol can be considered.
  • the target antioxidant active substance in the production method of the present invention can be produced by these reduction reactions or hydrolysis. As described above, in the present invention, it is possible to efficiently oxidize the ortho position of phenol of a compound such as piciferic acid using an available and inexpensive peroxide. As a result, an antioxidant active substance is produced with high efficiency. be able to.
  • the manufactured antioxidant active substance can be converted into carnosol and rosmanol by a known method.
  • carnosol can be produced when carnosic acid is oxidized by DDQ, silver oxide or air, and the quinone-quinone metide tautomer formed is lactonized.
  • Rosmanol can be produced by oxidation of carnosol with methylene chloride with pyridinium chlorochromate (PCC) or with air in the presence of sodium bicarbonate.
  • IBX As the oxidizing agent, IBX can be used, and the produced orthoquinone can be reduced to an ester group using a reducing agent such as sodium borohydride.
  • a reducing agent such as sodium borohydride.
  • the reaction formula is shown below.
  • carnosic acid can be produced by the following method for synthesizing carnosic acid using IBX.
  • Example 1 ⁇ Separation of piciferic acid> Sawara leaves (collected from the forest of Tokyo University of Agriculture and Technology, Harumi-cho, Fuchu-shi, Tokyo) were collected and used as starting materials. 160 g of the above Sawara leaves were weighed and refluxed in about 800 ml of methanol at about 65 ° C. for 24 hours. Next, the methanol extract obtained by the above refluxing operation was concentrated under reduced pressure, and then a liquid / liquid extraction operation was performed with ethyl acetate and water.
  • the ethyl acetate layer was concentrated, and the concentrate was subjected to column chromatography using silica gel and hexane / ethyl acetate (volume ratio 3: 1). After concentrating the fraction containing piciferin acid, perform column chromatography again in the same manner. The resulting fraction containing piciferin acid was crystallized using hexane / ethyl acetate (volume ratio 3: 1), and A certain 248 mg of piciferic acid was obtained.
  • the melting point and microstructure of the generated piciferin acid were measured by a melting point analyzer, 1 H-NMR, and 13 C-NMR, respectively.
  • the melting point measuring device used MEL-TEMP by Laboratory Device, and measured it on the conditions without correction
  • 1 H-NMR and 13 C-NMR measurements were performed using JEOL manufactured by JEOL Ltd. alpha-600 ( 1 H: 600 MHz, 13 C: 150.8 MHz) Using a spectrometer. Tetramethylsilane in deuterated chloroform was used as a standard.
  • FIG. 1 shows the analysis result of piciferic acid.
  • Piciferic acid 200 mg: 0.63 mmol was dissolved in methylene chloride (10 ml), and m-chlorobenzoyl peroxide (590 mg: 1.9 mmol) was added and dissolved. The solution was allowed to stand at room temperature under argon for 16 hours and then concentrated. The concentrated residue was dissolved in ethyl acetate, and hexane was added to separate the precipitated crystals. The mother liquor was further concentrated to obtain a mixture containing ortho-oxidized carnosic acid monoester.
  • the ester group was hydrolyzed under reductive conditions without further purification of the fraction containing carnosic acid monoester, and induced to a hydroxyl group.
  • a fraction (70 mg) containing carnosic acid monoester was dissolved in methanol (9 ml), 1% -NaOH (1 ml) and sodium borohydride (13.2 mg) were added, and the mixture was heated to reflux for 2 hours under argon.
  • the product was acidified with 1M hydrochloric acid and extracted with brine-ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated.
  • Example 2 ⁇ Synthesis of carnosic acid using chloroacetylmetachlorobenzoyl peroxide (CAMCBPO)> Chloroacetic acid (59.7 mg, 0.63 mmol) was dissolved in methylene chloride (15 ml), dicyclohexylcarbodiimide (DCC, 143.5 mg, 0.70 mmol) was added, and the mixture was stirred at 0 ° C. for 15 minutes under a stream of argon. mCPBA, 152.7 mg, 0.88 mmol) was added, and the mixture was stirred at 0 ° C.
  • DCC dicyclohexylcarbodiimide
  • Pisiferic acid was isolated and purified from Sawara in high yield, and this was ortho-oxidized to produce carnosic acid (Carnosic acid), the main antioxidant active substance of rosemary. It is understood that acid) can be produced efficiently.
  • the main antioxidant active substance of rosemary which has been attracting attention in recent years due to its preventive effect against Alzheimer's disease and various lifestyle-related diseases, is supplied from the leaves of Sawara planted in large quantities as wood resources. The technical significance is extremely large.
  • Example 4 ⁇ Measurement of antibacterial activity>
  • Carnosic acid (Example 4) which is the main antioxidant active substance of rosemary synthesized according to Example 1, and carsol (Example 5) synthesized from this carnosic acid were used for anti-methicillin-resistant Staphylococcus aureus activity (anti-MRSA). Activity) and anti-acne activity.
  • Acne (acne) is a chronic inflammatory disease that occurs in the skin from around puberty. Proliferation (infection) is thought to play an important role.
  • there are many types of antibacterial drugs for external use that have been approved for use as treatments for this disease, many of them are old, and few drugs can be applied to clinical treatment.
  • the measurement of anti-acne bacteria activity was performed as follows. That is, using the antioxidant substance obtained in Example 1 as a sample, diluting 10 times with Pluronic L44 (polyoxyethylene / polyoxypropylene), and diluting it 10% by weight in the medium for acne bacteria A sample was prepared at a concentration of 1.0% by weight. As a control, 10% by weight Pluronic L-44 was used. After acne bacteria were cultured in a GAM liquid medium for 24 hours, they were precipitated, and the GAM liquid medium was washed twice with an acne medium, and the sample was inoculated as an inoculum. Thereafter, the number of remaining bacteria was counted after 24 and 48 hours.
  • Pluronic L44 polyoxyethylene / polyoxypropylene
  • Counting was performed by serial dilution from 1.0 to 100,000 times using a medium for acne bacteria, and after anaerobic culture using a plate smearing method.
  • MRSA methicylene resistant Staphylococcus aureus
  • the main antioxidant active substance obtained by the method for producing the antioxidant active substance of the present invention has a remarkable antibacterial activity, and these results indicate that the antioxidant active substance of the present invention May be useful as a treatment for acne.
  • the method for producing an antioxidant active substance according to the present invention is a method for producing an antioxidant active substance using Sawara planted in large quantities as a wood resource, and can therefore contribute to the development of forestry and environmental technology fields. . Furthermore, the method for producing carnosic acid of the present invention can greatly contribute to technological innovation in the fields of medicine and medical technology.

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Abstract

L’invention concerne un procédé de fabrication d’acide carnosique (la substance active antioxydante majeure contenue dans une plante de romarin) avec une grande efficacité en réalisant l’oxydation en position ortho d’un phénol avec un oxydant (p. ex. acide 2-iodoxybenzoïque) et la réaction ultérieure d’élimination de l’ester en utilisant, en tant que matière première, de l’acide pisiférique (le composant principal de Chamaecyparis pisifera, qui est une plante qui a été plantée en nombres importants en tant que ressource de bois). L’invention concerne plus précisément un procédé de fabrication d’une substance active antioxydante contenue dans une plante de romarin et représentée par la formule générale (5). Le procédé est caractérisé en ce qu’il comprend : une première étape d’oxydation d’un dérivé d’acide pisiférique représenté par la formule générale (1) avec un oxydant représenté par la formule générale (2) ou (4) ; et une seconde étape de réduction ou d’hydrolyse d’un intermédiaire du dérivé d’acide pisiférique produit lors de la première étape.
PCT/JP2009/060547 2008-06-09 2009-06-09 Procédé de fabrication d’une substance active antioxydante WO2009151057A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
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JP2018537369A (ja) * 2015-09-24 2018-12-20 インターナショナル コンソリデーティッド ビジネス グループ ピーティーワイ リミテッド 抗酸化剤活性食品包装

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JP2006199666A (ja) * 2005-01-24 2006-08-03 Nagase & Co Ltd 健忘症の予防・治療剤
JP2007508320A (ja) * 2003-10-10 2007-04-05 アクセス ビジネス グループ インターナショナル エルエルシー マンネンロウ（Ｒｏｓｍａｒｉｎｕｓｏｆｆｉｃｉｎａｌｉｓ）植物抽出物、センテラ（Ｃｅｎｔｅｌｌａ）、ムラサキバレンギク（Ｅｃｈｉｎａｃｅａ）又はアルピニア（Ａｌｐｉｎｉａ）植物抽出物、及びＤＮＡ修復酵素を含む組成物

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JP2007508320A (ja) * 2003-10-10 2007-04-05 アクセス ビジネス グループ インターナショナル エルエルシー マンネンロウ（Ｒｏｓｍａｒｉｎｕｓｏｆｆｉｃｉｎａｌｉｓ）植物抽出物、センテラ（Ｃｅｎｔｅｌｌａ）、ムラサキバレンギク（Ｅｃｈｉｎａｃｅａ）又はアルピニア（Ａｌｐｉｎｉａ）植物抽出物、及びＤＮＡ修復酵素を含む組成物
JP2006199666A (ja) * 2005-01-24 2006-08-03 Nagase & Co Ltd 健忘症の予防・治療剤

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Title
MINOMIYA K. ET AL.: "Carnosic acid, a new class of lipid absorption inhibitor from sage", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 1943 - 1946 *
WALTER L. MEYER ET AL.: "Diterpenoid Total Synthesis, an A?B?C Approach. VIII. Introduction of Oxygen at Carbon-11. Total Synthesis of (±)-Carnosic Acid Dimethyl Ether and (±)-Carnosol Dimethyl Ether", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 41, no. 6, 1976, pages 1005 - 1015 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018537369A (ja) * 2015-09-24 2018-12-20 インターナショナル コンソリデーティッド ビジネス グループ ピーティーワイ リミテッド 抗酸化剤活性食品包装

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