JP5220403B2 - Method for producing dioxabicyclo [3.3.0] octane derivative having catechol group introduced - Google Patents

Description

  The present invention relates to a method for producing a dioxabicyclo [3.3.0] octane derivative having a catechol group useful as an antioxidant.

  Oxygen is indispensable for the living body, but when oxygen is reduced in vivo to a group of highly reactive molecular species called active oxygen, it oxidizes target molecules such as proteins, nucleic acids, and lipids in vivo. It is known to hurt. In order to prevent this damage caused by oxygen, living organisms prevent the oxidation of target molecules by keeping the amount of active oxygen generated low and further eliminating the generated active oxygen.

Polyphenolic compounds such as catechin, quercetin, and ellagic acid that are widely present in plants have a catechol group in the molecule and are generally considered to have antioxidant activity. However, many of the compounds such as sesamin, sesaminol, sesamorin, pyresinol, eudesmin, podophyllotoxin, etc., classified as lignan compounds, which are compounds obtained by oxidation polymerization of 2 units of C ₆ -C ₃ structure (phenylpropanoid), The phenol group or catechol group present in their chemical structure is protected as a methylenedioxy group or a methoxy group, and its antioxidant activity is weak. Therefore, various methods for deprotecting protected phenols, particularly catechol groups, in lignan compound molecules have been studied.

Non-Patent Document 1 describes that a methylenedioxyphenyl group can be converted into a catechol group by subjecting it to a decomposition reaction using aluminum bromide (AlBr ₃ ) and ethanethiol (CH ₃ CH ₂ SH). However, in Patent Document 1, when the above decomposition reaction is applied to a lignan compound having a methylenedioxyphenyl group and a benzyl ether group, such as sesamin, the benzyl position reacts preferentially and cleaves. It is described that the group cannot be generated. As a method for solving this problem, Patent Document 1 discloses a method of selectively hydrolyzing a methylenedioxy group present in a lignan compound molecule by using supercritical water. It has also been shown that lignan compounds having a catechol group obtained from sesamin and episesamin by this method have higher antioxidant activity than the raw materials sesamin and episesamin. However, this method requires a special apparatus that has a low reaction yield and can withstand high temperatures and high pressures to produce supercritical water.

  In Patent Documents 2 and 3, fermenting raw materials containing sesamin, sesaminol or sesaminol glycosides, which are lignan compounds having a methylenedioxyphenyl group and a benzyl ether moiety, are fermented using Aspergillus microorganisms. Describes that a sesamin catechol body, a sesamin dicatechol body or a sesaminol catechol body can be produced. However, according to the examples of these documents, the conversion rate from the raw material lignan compound to the corresponding catechol compound was not satisfactory although the fermentation process took a long time.

  As described above, the methods disclosed so far that can selectively remove the methylenedioxy group of the lignan compound having a methylenedioxyphenyl group have not been satisfactory in practice.

JP 2001-139579 A JP-A-2005-23125 JP 2005-22999 A Chem. Lett., 97, 1979

  An object of the present invention is to provide a simple and high-yield production method of a dioxabicyclo [3.3.0] octane derivative having a catechol group introduced therein.

  As a result of intensive studies to achieve the above object, the present inventors have found that dioxabicyclo [3.3.0] octane derivatives having a methylenedioxyphenyl group are converted to metal halides, particularly boron tribromide. Alternatively, it was found that a dioxabicyclo [3.3.0] octane derivative having a catechol group introduced therein can be obtained with good yield by acting boron trichloride at a low temperature, and the present invention has been completed.

That is, the present invention relates to the following.
1. Dioxabicyclo [3.3.0] octane derivative having methylenedioxyphenyl group, having the following formula (I):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ may be the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl Group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, nitro group, cyano group, trifluoromethyl group, substitution An alkenyl group which may have a group, an alkynyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent May have a benzyloxy group, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, an arylamino group which may have a substituent, or a substituent Good Rubiniru represents a group or an optionally substituted aryl ethynyl group; or,
At least one pair of adjacent groups of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ may be taken together to form a methylenedioxy group;
Here, the substituents which may be present on each of the above groups are halogen atom, hydroxyl group, alkyl group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group And at least one selected from the group consisting of a group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, a trifluoromethyl group, an aryl group, and a heteroaryl group. And a metal halide, the following formula (II):

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined for formula (I). ]
The manufacturing method of the dioxabicyclo [3.3.0] octane derivative in which the catechol group shown in FIG.
2. Dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group having the following formula (I ′):

[Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ may be the same or different, and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl Group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, nitro group, cyano group, trifluoromethyl group, substitution An alkenyl group which may have a group, an alkynyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent May have a benzyloxy group, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, an arylamino group which may have a substituent, or a substituent Good A reel vinyl group, or an arylethynyl group which may have a substituent;
At least one pair of adjacent groups of R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ may be taken together to form a methylenedioxy group;
Here, the substituents which may be present on each of the above groups are halogen atom, hydroxyl group, alkyl group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group And at least one selected from the group consisting of a group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, a trifluoromethyl group, an aryl group, and a heteroaryl group. And a metal halide, the following formula (II ′):

[Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are as defined for formula (I ′). ]
The manufacturing method of the dioxabicyclo [3.3.0] octane derivative in which the catechol group shown in FIG.
3. Metal halides are boron tribromide (BBr ₃ ), boron trichloride (BCl ₃ ), aluminum trichloride (AlCl ₃ ), titanium tetrachloride (TiCl ₄ ), germanium tetrachloride (GeCl ₄ ), indium trichloride ( InCl ₃ ), gallium trichloride (GaCl ₃ ), scandium trichloride (ScCl ₃ ), zirconium tetrachloride (ZrCl ₄ ), tellurium tetrachloride (TeCl ₄ ), gallium tribromide (GaBr ₃ ), germanium tetrabromide ( 3. The production method according to 1 or 2, which is one or more selected from the group consisting of GeBr ₄ ).
4). 4. The production method according to 3, wherein the metal halide is boron tribromide (BBr ₃ ) or boron trichloride (BCl ₃ ).
5. A compound in which the dioxabicyclo [3.3.0] octane derivative (II) or (II ′) into which the catechol group is introduced is represented by the following formula (III):

And / or a compound represented by the following formula (IV):

The manufacturing method in any one of 1-4 which is.
6). The amount of the metal halide is 1.0 to 10.0 equivalents of the dioxabicyclo [3.3.0] octane derivative of the formula (I) or the formula (I ′) having a methylenedioxyphenyl group as a raw material. The manufacturing method in any one of 1-5 which is.
7). The reaction of the dioxabicyclo [3.3.0] octane derivative of formula (I) or formula (I ′) having a methylenedioxyphenyl group with a metal halide is carried out in an organic solvent, The manufacturing method in any one of 1-6.
8). The manufacturing method in any one of 1-7 whose temperature of reaction is -100-0 degreeC.
9. The production according to any one of 1 to 8, wherein the dioxabicyclo [3.3.0] octane derivative of the formula (I) or the formula (I ′) having a methylenedioxyphenyl group is a lignan compound derived from sesame. Method.
10. 10. The production method according to 9, wherein the sesame-derived lignan compound is sesamin.
11. The following formula (V):

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined for formula (I). Or the compound of formula (V) and the following formula (VI):

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined for formula (I). ] And a metal halide are reacted to form the following formula (VII):

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined for formula (I). ] Is produced, The manufacturing method in any one of 1-9 characterized by the above-mentioned.
12 The compound of formula (V) is episesamin, the compound of formula (VI) is sesamin, and the compound of formula (VII) is represented by the following formula (IX):

The production method according to 11, which is dicatechol sesamin.

  The reaction utilized in the present invention is a one-step reaction that does not go through a plurality of reactions. Therefore, by using the method of the present invention, a dioxabicyclo [3.3.0] octane derivative having a catechol group introduced in a simple and large amount can be obtained.

  In the production method of the present invention, a dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group used as a starting material thereof can be easily obtained from, for example, a sesame-derived lignan compound available from natural products. It can be obtained. Therefore, the production method of the present invention is a very suitable method for producing a dioxabicyclo [3.3.0] octane derivative having a catechol group in a large amount at a low cost, and has, for example, high antioxidant activity. Sesamin catechol can be easily obtained in high yield.

BEST MODE FOR CARRYING OUT THE INVENTION

  The method for producing a dioxabicyclo [3.3.0] octane derivative into which a catechol group of the present invention has been introduced (hereinafter also referred to as the method of the present invention) is a dioxabicyclo [3. 3.0] It is characterized in that a metal halogen compound is allowed to act on an octane derivative, preferably in an organic solvent, preferably at a low temperature.

  Dioxabicyclo [3.3.0] octane derivatives having methylenedioxyphenyl groups of the following formulas (I) and (I ′) used as raw materials in the production method of the present invention:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are as defined above]. ]
And a dioxabicyclo [3.3.0] octane derivative having a catechol group having the following formulas (II) and (II ′) to be produced:

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are as defined above]. ]
, There are stereoisomers resulting from the configuration at the two carbon atoms to which the substituent on dioxabicyclo [3.3.0] octane binds and the two bridgehead carbons. The compounds of I), (I ′), (II) and (II ′) include all possible stereoisomers including such stereoisomers.

  In the formulas (I), (I ′), (II) and (II ′), “— (O) —” represents a bond between the dioxabicyclo [3.3.0] octane ring and the phenyl group. It indicates that it may be a single bond or an ether bond.

  In the method of the present invention, a known compound can be used as the starting compound of the formula (I) or (I ′). Examples of such compounds include lignan compounds derived from natural products or chemically synthesized. Specific examples include sesame-derived lignan compounds such as sesamin and sesaminol. Among these, sesamin and episesamin can be preferably used in the present invention. In the present invention, isomers of lignan compounds can also be used as raw materials.

  For example, in the method of the present invention, the formula (VIII) comprising sesamin and episesamin:

By reacting the compound with a metal halide,
The following formula (III) including a monocatechol form of sesamin known to have high antioxidant activity

Embedded image and / or the dicatechol form of sesamin known to have high antioxidant activity (IV)

The dicatechol body represented by this can be obtained.
In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  In the present specification, the “alkyl group” preferably means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group. Group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, 3-methylbutyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, and n -A hexyl group and the like are included.

  In the present specification, the “alkoxy group” means a linear or branched alkoxy group having preferably 1 to 6 carbon atoms, and has already been defined, for example, methoxy group, ethoxy group, n-propoxy group, etc. Having an alkyl group as an alkyl moiety.

Similarly, the “alkylthio group”, “alkylsulfonyl group”, and “alkylamino group” in the present specification have the alkyl group already defined as the alkyl moiety.
The “acyl group” in the present specification is, for example, an alkylcarbonyl group or an arylcarbonyl group, and includes a C _1-6 alkylcarbonyl group having a previously defined alkyl group as an alkyl moiety and a benzoyl group.

The “acyloxy group” in the present specification has an acyl group as defined above as an acyl moiety.
The “alkoxycarbonyl group” in the present specification has an alkoxy group as defined above as an alkoxy moiety.

  As used herein, the term “alkenyl group” means a straight or branched hydrocarbon group having 2 to 6 carbon atoms and having one or more double bonds, such as a vinyl group, 1 -Propenyl group, 2-propenyl group, 2-butenyl group, 1,3-butadienyl group, 2-pentenyl group, 3-pentenyl group, 2-hexenyl group and the like can be mentioned.

  The “alkynyl group” in the present specification preferably means a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a 1-propynyl group, and a 2-propynyl group. It is done.

  The “aryl group” in the present specification is a monocyclic to tetracyclic aromatic carbocyclic group having 6 to 18 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. A phenyl group is preferred.

  In the present specification, the “heteroaryl group” means a group containing a 5- or 6-membered aromatic ring having one or more heteroatoms in the ring, and may be condensed with another ring. Heteroatoms include nitrogen, oxygen, and sulfur. Heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, tetrazolyl, oxazolyl, indolizinyl, indolyl, isoindolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, azoxalylyl, azoxylylyl Examples include thiadiazolyl and benzimidazolyl.

  The “aryloxy group”, “arylamino group”, “arylvinyl group”, and “arylethynyl group” in the present specification have an aryl group that has already been defined as an aryl moiety.

A “heteroaryloxy group” herein has a heteroaryl group that has already been defined as a heteroaryl moiety.
The groups R _{1 to} R ₇ can be converted into other groups R _{1 to} R ₇ by modification by known methods in additional reaction steps. For example, a hydroxyl group, an amino group, and a mercapto group can be converted into an alkoxy group, an aminoalkyl group, and an alkylthio group, respectively, by a known method.

In this reaction, a reactive group may be appropriately protected with a protecting group. Any known method may be used for this purpose.
In the method of the present invention, a lignan compound such as sesamin that can be used as a starting material can be extracted from a raw material such as sesame oil by a method described in JP-A-3-27319, for example. Alternatively, a raw material containing a lignan compound, for example, sesame seeds, sesame seeds, sesame oil, or sesame deodorized scum can be used as a raw material.

Examples of the metal halide used in the reaction include boron tribromide (BBr ₃ ), boron trichloride (BCl ₃ ), aluminum trichloride (AlCl ₃ ), titanium tetrachloride (TiCl ₄ ), germanium tetrachloride (GeCl ₄ ), Indium trichloride (InCl ₃ ), gallium trichloride (GaCl ₃ ), scandium trichloride (ScCl ₃ ), zirconium tetrachloride (ZrCl ₄ ), tellurium tetrachloride (TeCl ₄ ), gallium tribromide (GaBr ₃ ), four Examples thereof include germanium bromide (GeBr ₄ ), among which BBr ₃ or BCl ₃ is preferably used. When a metal halide is used for the compound of formula (I) and / or formula (I ′) which is the starting material, catechol is cleaved by cleaving the methylenedioxy group while protecting the benzyl position, ie, suppressing the cleavage of the benzyl position. Groups can be introduced. The addition amount of the metal halide is usually 1.0 to 10.0 molar equivalents, preferably 4.0 to 8.0 molar equivalents relative to the starting compound.

  In the present invention, it is important to react the compound of formula (I) and / or (I ′) with a metal halide, and this reaction may be performed by adding other reactants such as a catalyst and a reaction accelerator. It is possible to proceed without using. Although additional reactants may be used in some cases, it is not preferable to use substances that can adversely influence the reaction of the present invention, for example, thiols such as ethanethiol described in Patent Document 1 (benzyl). Likely to cause cleavage of the ether).

  The solvent may be appropriately used as long as it is inert in the reaction. Examples of the organic solvent used in the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and dichlorobenzene; pentane, hexane, cyclopentane, Aliphatic hydrocarbons such as cyclohexane and the like can be mentioned, among which dichloromethane is preferable. The amount of the organic solvent is usually 10 to 100 parts by weight of the solvent with respect to 1 part by weight of the starting compound.

In the method of the present invention, the starting material (dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group) is preferably dissolved in an organic solvent and kept at a low temperature, and then a metal halide is added. To do. The metal halide is preferably added as a reaction solution dissolved in an organic solvent. The concentration of the reaction solution is preferably 0.1 to 0.5 mol / L, and more preferably 0.1 to 0.3 mol / L. This concentration is particularly effective when dichloromethane is used as the organic solvent and BBr ₃ is used as the metal halide.

  The process according to the invention is characterized in that a metal halide is allowed to act on the starting material at a low temperature for a short time. As described above, the reaction solution (the one obtained by adding an organic solvent to a metal halide) is preferably added to a raw material solution (one obtained by adding an organic solvent to a starting material) that is maintained at a low temperature in advance. The low temperature referred to in the present invention is about −100 to 0 ° C., preferably about −78 to −20 ° C.

  In the method of the present invention, the reaction is preferably maintained at a low temperature within the above range. Since the product of the reaction of the present invention is generally unstable to acids and bases, the reaction is desirably performed at 0 ° C. or lower. In addition, since dichloromethane, which is often used as a reaction solvent, has a melting point of −97 ° C., it is desirable to react at a temperature higher than that. Further, at an extremely low temperature of −100 ° C. or lower, a decrease in the yield of the dioxabicyclo [3.3.0] octane derivative having a catechol group introduced therein is observed. In the method of the present invention, in order to maintain the reaction temperature and to uniformly perform the reaction, it is preferable to perform stirring when maintaining the raw material liquid at a low temperature or when performing the reaction.

  The reaction time varies depending on the type and concentration of the metal halide, the reaction temperature, and the like, but is usually 0.5 to 10 minutes, preferably about 1 to 5 minutes. Thus, the method of the present invention is characterized in that it is completed in a very short time. The end point of the reaction is carried out while confirming the amount of raw materials and / or products by a method such as TLC, and a dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group as a starting material. The end point of the reaction may be the point at which is completely or almost completely consumed. The reaction can be stopped by a known post-treatment such as adding an alcohol or a water-containing organic solvent to the reaction solution.

  After completion of the reaction, the dioxabicyclo [3.3.0] octane derivative having the target catechol group is obtained by a known method such as purification by HPLC after removing the organic solvent under reduced pressure.

According to the method of the present invention, when there are two or more methylenedioxyphenyl groups of the starting dioxabicyclo [3.3.0] octane derivative, the compound obtained by controlling the degree of reaction It is also possible to control the properties. Specifically, it can be controlled by adjusting the amount of metal halide. For example, when a dioxabicyclo [3.0.0] octane derivative of the formula (VIII) including sesamin is used as a raw material, the monocatechol body represented by the above formula (III) and the formula (IV) are usually used. It has been confirmed by the present inventors that their production ratio varies depending on the amount of metal halide used. For example, when sesamin is used as a starting material, BBr ₃ is used as a metal halide, and dichloromethane is used as an organic solvent, if the amount of BBr ₃ is increased, sesamin dicatechol body (dicatechol sesamin) is selectively used. Obtained. Specifically, when 3.5 to 8.0 equivalents of BBr ₃ of sesamin is used, dicatechol sesamin can be obtained almost selectively, and when BBr ₃ is low, specifically 2 of sesamin. When 0 to 3.0 equivalents of BBr ₃ was used, sesamin monocatechol body (monocatechol sesamin) corresponding to 20 to 30% by weight of the product was obtained.

  In the method of the present invention, dicatechol sesamin is the main product not only when sesamin is used as a starting material, but also when episesamin, which is an isomer of sesamin, and when a mixture of sesamin and episesamin is used. As a by-product, dicatechol episesamin was obtained. Therefore, the method of the present invention can be particularly suitably used for the production of a compound of formula (VII) containing dicatechol sesamin.

(Use of dioxabicyclo [3.3.0] octane derivative having a catechol group introduced)
The dioxabicyclo [3.3.0] octane derivative introduced with the catechol group obtained by the method of the present invention has various effects such as carcinogenesis, inflammation, ischemic organ damage, arteriosclerosis caused in the body by the influence of active oxygen. It can be used as an active ingredient of a composition for the treatment and / or prevention of disorders, diseases and aging. The administration route of the antioxidant composition is most preferably oral administration, but may be intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, or the like. Formulations suitable for oral administration include, but are not limited to, tablets, capsules, powders, granules, solutions, syrups and the like. For therapeutic and / or prophylactic compositions, as a pharmaceutically acceptable carrier, suitable excipients, binders, disintegrants, lubricants, flavoring agents, coloring agents, solubilizing aids known in the art. Agents, suspensions, coatings and the like may be included.

  The composition can also be used as a topical pharmaceutical or cosmetic for transdermal administration to treat or ameliorate various skin or mucosal conditions such as skin or mucosal aging, carcinogenesis or inflammation, or skin tanning. . Dosage forms suitable as topical pharmaceuticals or cosmetics include solutions, poultices, patches and the like. The external medicine may contain an excipient, a flavoring agent, a coloring agent, a solubilizing agent, a suspending agent and the like as a pharmaceutically acceptable carrier.

  The composition can also be provided in the form of food. Preferred food forms include powders, granules, pastes, jellies and the like. In particular, in the case of granules or the like, sugars such as lactose can be added to add sweetness. Moreover, the said composition can also be provided with the form of a drink. In addition to the dioxabicyclo [3.3.0] octane derivative into which a catechol group is introduced, such a food or beverage may be supplemented with vitamins, inorganic components such as calcium, alcohols, and the like. The food or beverage includes food for specified health use, food for the sick, and the like.

  The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. It is possible for those skilled in the art to use the method of the present invention with various changes and modifications, and these are also included in the scope of the present invention.

Example 1
Catechol synthesis

In an eggplant-shaped flask, 0.5 mL of dichloromethane was added, and 8.8 mg (0.025 mmol) of sesamin was dissolved with stirring. The flask was immersed in a -78 ° C refrigerant and cooled, then a BBr ₃ / dichloromethane solution (1 mol / L) was added, and the mixture was stirred at -78 ° C for 2 minutes. This reaction was performed nine times with varying amounts of the BBr ₃ / dichloromethane solution (0.025-0.2 mL (1.0-8.0 molar equivalents)). Moreover, the same reaction was performed using episesamin or a mixture of sesamin and episesamin as a raw material.

  Thereafter, 0.5 mL of 2-propanol was added to each reaction flask to prepare a solution for HPLC analysis. A certain amount of the HPLC analysis solution kept at −78 ° C. was diluted with 1 mL of 80% acetonitrile aqueous solution (containing 1% formic acid), and SC-2 (dicatechol sesamin: Retention time 21.5 minutes), the amount of SC-1 (monocatechol sesamin: retention time 37.3 minutes) and EC-2 (dicatechol episesamin: retention time 24.7 minutes) obtained together, and The amount of unreacted sesamin (retention time 41.7 minutes) was analyzed. The HPLC retention times of these components coincided with the retention times of the corresponding samples. These preparations can be obtained by a known method, for example, the method described in Patent Document 1. SC-1, SC-2 and EC-2 used as preparations in this example were synthesized separately by the method of the present invention and identified by NMR and mass spectrometry.

HPLC conditions:
Column: DAISOPAK SP-120-5-ODS-AP (φ4.6 × 150mm, Daicel Chemical Industries, Ltd.)
Flow rate: 1.0 mL / min Gradient: B solution 0-80% (0-30 minutes)
Solvent A: H ₂ O (containing 0.1% trifluoroacetic acid)
Solvent B: CH ₃ CN-H ₂ O (9: 1) solution (containing 0.1% trifluoroacetic acid)
Detection wavelength: 280nm
Measurement time: 60 minutes Table 1 shows the results of the HPLC analysis.

The results of accurate mass spectrometry for each product are as follows. These values almost coincided with the values of the respective standard products.
SC-1: ESI-IT-TOF-MS m / z 341.1028 [M−H] ⁻
(Theoretical value of C ₁₉ H ₁₇ O ₆ : 341.015)
SC-2: ESI-IT-TOF-MS m / z 329.1034 [M−H] ⁻
(Calculated for _{C 18 H 17 O 6: 329.1025} )
EC-2: ESI-IT-TOF-MS m / z 329.1028 [M−H] ⁻
(Calculated for _{C 18 H 17 O 6: 329.1025} )

  It was confirmed that monocatechol sesamin and dicatechol sesamin can be obtained by the method of the present invention.

In addition, in order to produce monocatechol sesamin, it has become clear that it is preferable to use 2.0 to 3.0 molar equivalents of BBr ₃ as the starting material (sesamin). When BBr ₃ is 3 molar equivalents or less, a large amount of unreacted starting material (sesamin) remains. Therefore, in order to efficiently obtain monocatechol sesamin, BBr ₃ is adjusted to 2.5 to 3.0. It has become clear that it is preferable to use molar equivalents.

When dicatechol sesamin is produced, it is preferable to use 2.0 equivalents or more of BBr ₃ of the starting material (sesamin), particularly 3.5 to 8.0 equivalents, preferably 4.0 to 5 equivalents. It was found that the use of 0.0 molar equivalent of BBr ₃ can reduce the amount of by-products containing monocatechol. When BBr ₃ was used in a large amount (8 molar equivalents or more), the yield tended to decrease.

  Furthermore, not only when sesamin is used as a starting material, but also when episesamin, which is an isomer of sesamin, or a mixture of sesamin and episesamin is used, dicatechol sesamin is obtained as the main product, and in any case It was found that a small amount of dicatechol episesamin was formed.

  Therefore, it can be said that the method of the present invention can be suitably used for the production of a compound of formula (VII) including a dicatechol body, particularly dicatechol sesamin.

Example 2
Synthesis and isolation of dicatechol body 0.5 mL of dichloromethane was placed in an eggplant-shaped flask, and 8.8 mg (0.025 mmol) of sesamin was dissolved with stirring. The flask was immersed in a −78 ° C. refrigerant and cooled, and 0.1 mL (4.0 molar equivalent) of a BBr ₃ / dichloromethane solution (1 mol / L) was added, followed by stirring at −78 ° C. for 3 minutes. Thereafter, 0.2 mL of 2-propanol was added to the liquid in the flask, and the mixture was stirred at −78 ° C. for 2 minutes. In order to remove most of the dichloromethane in the solution, the solution cooled to −78 ° C. was attached to a vacuum pump, and the dichloromethane was removed while gradually raising the temperature to 0 ° C. Then, the residue was dissolved in 0.5 mL of 50% aqueous acetonitrile (containing 1% formic acid), and this solution was subjected to HPLC to obtain dicatechol sesamin (3.0 mg, 36.4%). Thus, even when dicatechol sesamin was isolated and purified, the same yield as the HPLC analysis result (%) shown in Example 1 was achieved.

Preparative HPLC conditions:
Column: DAISOPAK SP-120-5-ODS-AP (φ20.0 × 250mm, Daicel Chemical Industries, Ltd.)
Flow rate: 9.999 ml / min Gradient: 0-80% B / 50 min Solvent A: H ₂ O (containing 0.1% trifluoroacetic acid)
Solvent B: CH ₃ CN-H ₂ O (9: 1) solution (containing 0.1% trifluoroacetic acid)
Detection wavelength: 280nm
Preparative fraction: 18.0 to 19.8 minutes

  The resulting dicatechol sesamin was subjected to HPLC analysis and accurate mass analysis under the conditions shown in Example 1. As a result, HPLC retention time (21.4 minutes) and accurate mass number (m / z: 329.1025) were obtained. It was also confirmed that it was consistent with the standard.

Example 3
Synthesis of catechol body with BCl ₃ 0.5 mL of dichloromethane was placed in an eggplant-shaped flask, and 8.8 mg (0.025 mmol) of sesamin was dissolved with stirring. The flask was immersed in a −78 ° C. refrigerant and cooled, and then 0.1 mL (4.0 equivalents) of a BCl ₃ / dichloromethane solution (1 mol / L) was added, followed by stirring at −78 ° C. for 2 minutes. Thereafter, 0.5 mL of 2-propanol was added to the flask to prepare a solution for HPLC analysis. A certain amount of the solution for HPLC analysis kept at −78 ° C. was diluted with 1 mL of 80% acetonitrile aqueous solution (containing 1% formic acid) and subjected to HPLC analysis under the conditions shown in Example 1, SC-2 (dicatechol). Sesamin: retention time 21.5 minutes) was confirmed to be produced in a yield of 19.4%.

Claims (13)

A dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group , represented by the following formula (I):
[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ may be the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl Group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, nitro group, cyano group, trifluoromethyl group, substitution An alkenyl group which may have a group, an alkynyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent May have a benzyloxy group, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, an arylamino group which may have a substituent, or a substituent Good Rubiniru represents a group or an optionally substituted aryl ethynyl group; or,
At least one pair of adjacent groups of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ may be taken together to form a methylenedioxy group;
Here, the substituents which may be present on each of the above groups are halogen atom, hydroxyl group, alkyl group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group And at least one selected from the group consisting of a group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, a trifluoromethyl group, an aryl group, and a heteroaryl group. And a metal halide without the use of thiols, the following formula (II):
[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ are as defined for formula (I). ]
The manufacturing method of the dioxabicyclo [3.3.0] octane derivative in which the catechol group shown in FIG. Dioxabicyclo [3.3.0] octane derivative having a methylenedioxyphenyl group , represented by the following formula (I ′):
[Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ may be the same or different, and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, or an alkyl Group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group, alkoxycarbonyl group, carbamoyl group, nitro group, cyano group, trifluoromethyl group, substitution An alkenyl group which may have a group, an alkynyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, and a substituent May have a benzyloxy group, an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, an arylamino group which may have a substituent, or a substituent Good A reel vinyl group, or an arylethynyl group which may have a substituent;
At least one pair of adjacent groups of R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ may be taken together to form a methylenedioxy group;
Here, the substituents which may be present on each of the above groups are halogen atom, hydroxyl group, alkyl group, mercapto group, alkoxy group, alkylthio group, alkylsulfonyl group, acyl group, acyloxy group, amino group, alkylamino group, carboxyl group And at least one selected from the group consisting of a group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, a trifluoromethyl group, an aryl group, and a heteroaryl group. And a metal halide without the use of thiols, the following formula (II ′):
[Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ are as defined for formula (I ′). ]
The manufacturing method of the dioxabicyclo [3.3.0] octane derivative in which the catechol group shown in FIG. Metal halides are boron tribromide (BBr ₃ ), boron trichloride (BCl ₃ ), aluminum trichloride (AlCl ₃ ), titanium tetrachloride (TiCl ₄ ), germanium tetrachloride (GeCl ₄ ), indium trichloride ( InCl ₃ ), gallium trichloride (GaCl ₃ ), scandium trichloride (ScCl ₃ ), zirconium tetrachloride (ZrCl ₄ ), tellurium tetrachloride (TeCl ₄ ), gallium tribromide (GaBr ₃ ), germanium tetrabromide ( GeBr is one or more members selected from the group consisting of ₄₎ the method according to claim 1 or 2. The production method according to claim 3, wherein the metal halide is boron tribromide (BBr ₃ ) or boron trichloride (BCl ₃ ). A compound in which the dioxabicyclo [3.3.0] octane derivative (II) or (II ′) into which the catechol group is introduced is represented by the following formula (III):
And / or a compound represented by the following formula (IV):
The manufacturing method in any one of Claims 1-4 which is these. The amount of the metal halide is 1.0 to 10.0 mol of the dioxabicyclo [3.3.0] octane derivative represented by the formula (I) or the formula (I ′) having a methylenedioxyphenyl group as a raw material. The manufacturing method in any one of Claims 1-5 which is an equivalent. The amount of the metal halide is 2.0 to 10.0 mol of the dioxabicyclo [3.3.0] octane derivative represented by the formula (I) or the formula (I ′) having a methylenedioxyphenyl group as a raw material. The manufacturing method of Claim 6 which is an equivalent. The amount of the metal halide is 2.0 to 3.0 mol of the dioxabicyclo [3.3.0] octane derivative represented by formula (I) or formula (I ′) having a methylenedioxyphenyl group as a raw material. The manufacturing method of Claim 6 which is an equivalent. A reaction between a dioxabicyclo [3.3.0] octane derivative represented by formula (I) or formula (I ′) having a methylenedioxyphenyl group and a metal halide is performed in an organic solvent. The manufacturing method in any one of Claims 1-8 . The temperature of the reaction is -100~0 ℃, process according to any one of claims 1-9. Dioxabicyclo [3.3.0] octane derivative represented by the formula (I) or formula (I ') having a methylenedioxyphenyl group, a lignan compound from sesame, to claim 1-10 The manufacturing method as described. The manufacturing method of Claim 11 whose lignan compound derived from sesame is sesamin. The following formula (V):
Compounds wherein ^{shown, R 1, R 2, R} 3, R 4, R 5, R 6, R 7, R 8 are as defined for formula (I). Or a compound represented by the formula (V) and the following formula (VI):
Compounds wherein ^{shown, R 1, R 2, R} 3, R 4, R 5, R 6, R 7, R 8 are as defined for formula (I). And a metal halide without using a thiol, the following formula (VII):
Compounds wherein ^{shown, R 1, R 2, R} 3, R 4, R 5, R 6, R 7, R 8 are as defined for formula (I). ], Characterized in that to produce the method according to any one of claims 1 to 11.