JP7089274B2 - Oligomer containing epigallocatechin and its production method - Google Patents

Description

The present invention relates to a trimer or higher oligomer containing epigalotekin and a simple method for producing the same.

Compounds in which two or more flavonoids such as epigallocatechin are polymerized are collectively called prodelphinidin, which has physiological effects such as antioxidant action, antitumor action, carcinogenesis inhibitory action, and glucosidase inhibitory action, and is a material for health foods and cosmetics. It is widely used as.

Examples of prodelphinidin include prodelphinidin B1 having a structure of epigallocatechin- (β4 → 8) -gallocatechin, epigallocatechin- (β4 → 8) -prodelphidin B2 having a structure of gallocatechin- (α4). → 8) -Prodelphinidin B3 having a catechin structure, gallocatechin- (α4 → 8) -prodelphinidin B having an epigallocatechin structure, and the like are known.

In addition, due to the recent increase in health consciousness and naturalism consciousness, various studies on naturally occurring physiologically active substances are being promoted. For example, flavonoids and polyphenols of Okura show glycosidase inhibitory action, and vitamin C. It has been confirmed that it exhibits an antioxidant effect similar to that of BHA, which is an antioxidant. In addition, it has been confirmed that one of the polyphenols contained in okra is prodelphinidin, which is a polymer mainly composed of epigallocatechin, although there are few data on the specific structure.

However, the polymers of proanthocyanidins that have been reported to be produced so far have mainly been composed of catechin or epicatechin. Therefore, there has been a demand for a production method capable of efficiently producing epigallocatechin and gallocatechin oligomers such as prodelphinidin, which are not limited to catechin or epicatechin.

Prodelphinidin has a physiological activity not found in galocatechin or epigallocatechin monomers, and it is expected that the higher the degree of polymerization of the oligomer, the stronger the physiological activity. Therefore, several methods have been proposed so far as a method for producing prodelphinidins from flavonoids such as epigallocatechin (see, for example, Non-Patent Documents 1 and 2).

In Non-Patent Document 1, galocatechin is converted into two reactive derivatives, an electrophile and a nucleophile, by a known method, and Yb (OTf) ₃ is used as a catalyst at room temperature (for example, 23 ° C), respectively. A method for optically selectively obtaining a procidelphinidin B3 derivative from a product obtained by reacting in an amount-by-quantity manner is disclosed.

Further, in Non-Patent Document 2, two kinds of reactive derivatives similarly converted from gallocatechin and epigallocatechin are reacted optically selectively by reacting in equal amounts with Yb (OTf) ₃ as a catalyst. Methods for deriving to derivatives of catechins are disclosed.

Further, Non-Patent Document 3 discloses a method for dimerizing a reactive derivative converted from epigallocatechin by self-condensation.

As described above, prodelphinidin is a component that is abundantly contained in plants, but it has been difficult to obtain a high-purity compound because of its complicated structure and chemical instability. In particular, the higher the degree of polymerization, the more difficult it was to manufacture.

Therefore, although okra contains components showing useful physiological activity, it is rarely used in processed foods. Therefore, it is expected that new applications focusing on the physiologically active substances contained in okra will be expanded. However, it was difficult to produce a specimen for confirming the physiological activity, and research on the physiological activity could not proceed.

Therefore, Patent Document 1 describes metal trifurates, preferably itterbium trifurates (Yb (OTf) ₃ ), indium trifurates (In (OTf) ₃ ), copper trifurates (Cu (OTf) ₂ ), and lanthanum trifurates (La) as reaction catalysts. (OTf) ₃ ) or scandium trifurate (Sc (OTf) ₃ ) or boron compound, preferably silver tetrafluorinated (AgBF ₄ ) or tris (pentafluorophenyl) boron (B (C ₆ F ₅ ) ₃ ). It is shown that the dimer of catechin or epicatechin can be produced by reacting the electrophoric agent with the reactive derivative of the catechin or epicatechin monomer of the nucleophile in the presence of the electrophoric compound. Here, "metal triflate" means a salt of trifluoromethanesulfonic acid and a metal.

In addition, epicatechin 4 is reacted in the presence of zinc trifurate (Zn (OTf) ₃ ) using an epicatechin dimer as a nucleophile and an epicatechin 2 to tetramer as an electrophile. It is disclosed that a hexamer can be produced (Patent Document 2).

Further, a dimer condensate is obtained by reacting with an epicatechin protectant as a production raw material and using zinc trifurate as a reaction catalyst in methylene chloride, and zinc is further used as a reaction catalyst with another dimer. A technique for leading to a tetramer condensate by reacting with a triflate is disclosed (Patent Document 3).

Japanese Unexamined Patent Publication No. 2007-84536 Japanese Unexamined Patent Publication No. 2016-23156 Japanese Unexamined Patent Publication No. 2017-01982

K. Kron et al. , Eur. J. Org. Chem. , 2010, 69, 2544-2554. H. Makabe et al. , Tetrahedron, 2013, 69, 3543-3550. H. Makabe et al. , Tetrahedron Lett. , 2013, 54, 7188-7192. H. Makabe et al. , Synthesis, 2014, 46, 3351-3355.

However, according to the production method described in Patent Documents 1 to 3, epigallo using metal triflate, silver tetrafluorinated (AgBF ₄ ) or tris (pentafluorophenyl) boron (B (C ₆ F ₅ ) ₃ ). Even if an attempt is made to produce a trimer of catechin, it has not been possible to produce it with a sufficient yield and purity so that detailed structure and quantitative analysis can be performed.

Therefore, an object of the present invention is to provide a trimeric or more epigallocatechin oligomer and a synthetic method capable of easily producing the same. Further, by elucidating the physiological activity of the oligomer obtained by this production method, the purpose is to expand new applications focusing on the physiological activity of prodelphinidin contained in okra and the like.

（２）前記Ｒ１～Ｒ２３が、それぞれ独立して、芳香族炭化水素基又は脂肪族炭化水素基である、（１）に記載の化合物。
（３）前記Ｘ１およびＸ２が、それぞれ独立して、アシル基、置換アシル基、ベンジル基、置換ベンジル基、アルキル基、アリールアルキル基又は置換アリールアルキル基である、（１）または（２）に記載の化合物。
（４）下記一般式（ＶＩＩ）で表される、（１）に記載の化合物。

（５）（１）に記載の化合物を製造する製造方法であって、下記一般式（Ｉ）（式中、Ｒ１～Ｒ１０はフェノール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、Ｘ１～Ｘ２はアルコール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、Ｙは脱離基）で表される化合物を、下記一般式（Ｖ－１）または（Ｖ－２）（式中、Ｒ１１～Ｒ２４はフェノール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、ｎは１以上９以下の整数）で表される化合物と縮合させる工程を含む、製造方法。

（６）前記Ｙが、アルキルオキシ基、アルキルオキシアルキルオキシ基又はアリールアルキルオキシ基である、（５）に記載の製造方法。
（７）前記Ｙがエチレングリコールである、（６）に記載の製造方法。
（８）前記縮合をルイス酸の存在下で行う、（５）～（７）のいずれかに記載の製造方法。
（９）前記ルイス酸はイッテルビウムトリフラート（Ｙｂ（ＯＴｆ）_３）である、（８）に記載の製造方法。
（１０）前記縮合を０°Ｃ以上２３°Ｃ以下で行う、（５）～（９）のいずれかに記載の製造方法。
（１１）前記Ｒ１～Ｒ２４及び前記Ｘ１～Ｘ２で表される保護基を脱保護する反応工程を更に含む、（５）に記載の製造方法。
（１２）下記一般式（ＩＩＩ）（式中、Ｒ１～Ｒ１４はフェノール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基または水素、Ｘ１～Ｘ２はアルコール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基または水素、波線で表される結合は実線または破線のくさび形結合）で表される化合物。

（１３）前記Ｒ１～Ｒ１４が、それぞれ独立して、芳香族炭化水素基又は脂肪族炭化水素基である、（１２）に記載の化合物。
（１４）前記Ｘ１およびＸ２が、それぞれ独立して、アシル基、置換アシル基、ベンジル基、置換ベンジル基、アルキル基、アリールアルキル基又は置換アリールアルキル基である、（１２）または（１３）に記載の化合物。
（１５）前記Ｚが、水酸基、又は水素である、（１２）～（１４）のいずれかに記載の化合物。
（１６）下記一般式（ＩＶ）で表される、（１２）に記載の化合物。

（１７）（１２）に記載の化合物を製造する方法であって、下記一般式（Ｉ）（式中、Ｒ１～Ｒ１０はフェノール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、Ｘ１～Ｘ２はアルコール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、Ｙは脱離基）で表される化合物を、単離・精製することなく、下記一般式（ＩＩ）（式中、Ｒ１１～Ｒ１４はフェノール性水酸基の保護基として使用される基の中からそれぞれ独立して選択される任意の保護基、Ｚは水酸基または水素、波線で表される結合は実線又は破線のくさび形結合）で表される化合物と縮合させる工程を含む、製造方法。

（１８）前記Ｙが、アルキルオキシ基、アルキルオキシアルキルオキシ基又はアリールアルキルオキシ基である、（１７）に記載の化合物。
（１９）前記縮合をルイス酸の存在下で行う、（１７）または（１８）に記載の製造方法。
（２０）前記ルイス酸はイッテルビウムトリフラート（Ｙｂ（ＯＴｆ）_３）である、（１９）に記載の製造方法。
（２１）前記縮合を０°Ｃ以上２３°Ｃ以下で行う、（１７）～（２０）のいずれかに記載の製造方法。
（２２）前記Ｒ１～Ｒ１４及び前記Ｘ１～Ｘ２で表される保護基を脱保護する反応工程を更に含む、（１７）に記載の製造方法。 The present invention relates to the following contents.
(1) The following general formula (VI) (in the formula, R1 to R23 are arbitrary protecting groups or hydrogens independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcohols. An arbitrary protecting group or hydrogen, which is independently selected from the groups used as a protecting group for a sex hydroxyl group, and n is an integer of 1 or more and 10 or less).

(2) The compound according to (1), wherein R1 to R23 are independently aromatic hydrocarbon groups or aliphatic hydrocarbon groups.
(3) In (1) or (2), the X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, arylalkyl groups or substituted arylalkyl groups, respectively. The compound described.
(4) The compound according to (1), which is represented by the following general formula (VII).

(5) In the production method for producing the compound according to (1), the following general formula (I) (in the formula, R1 to R10 are independent of the groups used as the protective group for the phenolic hydroxyl group, respectively. X1 to X2 are arbitrary protective groups independently selected from the groups used as protective groups for alcoholic hydroxyl groups, and Y is a desorbing group). The following general formula (V-1) or (V-2) (in the formula, R11 to R24 are arbitrary protective groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, respectively. A production method comprising a step of condensing with a compound represented by (n is an integer of 1 or more and 9 or less).

(6) The production method according to (5), wherein Y is an alkyloxy group, an alkyloxyalkyloxy group or an arylalkyloxy group.
(7) The production method according to (6), wherein Y is ethylene glycol.
(8) The production method according to any one of (5) to (7), wherein the condensation is carried out in the presence of Lewis acid.
(9) The production method according to (8), wherein the Lewis acid is ytterbium triflate (Yb (OTf) ₃ ).
(10) The production method according to any one of (5) to (9), wherein the condensation is carried out at 0 ° C or higher and 23 ° C or lower.
(11) The production method according to (5), further comprising a reaction step of deprotecting the protecting groups represented by R1 to R24 and X1 to X2.
(12) In the following general formula (III) (in the formula, R1 to R14 are arbitrary protecting groups or hydrogens independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcohols. Any protective group independently selected from the groups used as the protective group for the sex hydroxyl group, or a compound represented by hydrogen or a wavy line (solid or broken wedge-shaped bond).

(13) The compound according to (12), wherein R1 to R14 are independently aromatic hydrocarbon groups or aliphatic hydrocarbon groups.
(14) In (12) or (13), the X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, arylalkyl groups or substituted arylalkyl groups, respectively. The compound described.
(15) The compound according to any one of (12) to (14), wherein Z is a hydroxyl group or hydrogen.
(16) The compound according to (12), which is represented by the following general formula (IV).

(17) In the method for producing the compound according to (12), the following general formula (I) (in the formula, R1 to R10 are independently from the groups used as protective groups for phenolic hydroxyl groups, respectively. Arbitrary protective groups selected, X1 to X2 are arbitrary protective groups independently selected from the groups used as protective groups for alcoholic hydroxyl groups, and Y is a desorbing group). , Z, which is an arbitrary protective group independently selected from the groups used as the protective group for the phenolic hydroxyl group in the following general formula (II) (in the formula, R11 to R14) without isolation and purification. Is a production method comprising a step of condensing with a compound represented by a hydroxyl group or hydrogen, and a bond represented by a wavy line is a wedge-shaped bond represented by a solid line or a broken line).

(18) The compound according to (17), wherein Y is an alkyloxy group, an alkyloxyalkyloxy group or an arylalkyloxy group.
(19) The production method according to (17) or (18), wherein the condensation is carried out in the presence of Lewis acid.
(20) The production method according to (19), wherein the Lewis acid is ytterbium triflate (Yb (OTf) ₃ ).
(21) The production method according to any one of (17) to (20), wherein the condensation is carried out at 0 ° C or higher and 23 ° C or lower.
(22) The production method according to (17), further comprising a reaction step of deprotecting the protecting groups represented by R1 to R14 and X1 to X2.

According to the present invention, a pure oligomer of a trimer or more containing epigallocatechin can be easily synthesized. Furthermore, oligomers of epicatechin-containing heterogas trimers or more containing catechin or epicatechin as a part can also be realized.

The epigalocatechin-containing heterogas oligomer obtained by carrying out the present invention, which partially contains catechin and epicatechin, has an antioxidant effect, an antiviral effect, an antibacterial effect, and an antitumor effect, similarly to conventional procyanidins. It is expected to exhibit physiological effects such as arteriosclerosis inhibitory effect, gastric ulcer inhibitory effect, carcinogenesis inhibitory effect, hair growth activating effect, and whitening effect, and is useful as a material for health foods and cosmetics.

FIG. 1 is a diagram showing the mechanism of the condensation reaction of epigallocatechin dimer. FIG. 2 is a structural formula of epigallocatechin trimer, tetramer and pentamer. FIG. 3 is a reaction formula of the epigalocatechin tetramer according to Preparation Example 4. FIG. 4 is a reaction formula of the epigalocatechin pentamer according to Preparation Example 5.

Hereinafter, the present invention will be described with reference to embodiments, but the present invention is not limited to the following embodiments.

[Compound]
The compound according to this embodiment is represented by the following general formula (VI). Here, in the formula (VI), R1 to R23 are arbitrary protecting groups or hydrogens independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are protections for alcoholic hydroxyl groups. Represents any protecting group or hydrogen, each independently selected from the groups used as a group, where n is an integer greater than or equal to 1. In addition, in this embodiment, it is not limited to epigalocatechin 4, pentamer.

[Production method]
The production method according to the present embodiment includes, for example, a step of condensing a compound represented by the following general formula (I) with a compound represented by the following general formula (V-1) or (V-2). Here, in the formula (I), R1 to R10 are arbitrary protecting groups independently selected from the groups used as protecting groups for phenolic hydroxyl groups, and X1 to X2 are protecting groups for alcoholic hydroxyl groups. Any protecting group independently selected from the groups used, Y represents a leaving group. Further, in the formula (V-1) or (V-2), R11 to R24 are arbitrary protecting groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, and n is 1 or more. Represents an integer of.

In the production method according to the present embodiment, the dimer of epigallocatechin represented by the general formula (I) is used as an electrophile, and the target product can be produced in high yield at room temperature or lower. This is the first discovery by the present inventors.

In the production method according to this embodiment, when producing a pentamer or more epigallocatechin oligomer, a trimer epigallocatechin oligomer represented by the above general formula (V-2) is required as a raw material. In some cases, the epigallocatechin trimer or a method for producing the same will be described later as an example.

In the formula (VI), R1 to R23 are arbitrary protective groups selected from the groups used as protective groups for phenolic hydroxyl groups, which may be the same or different from each other, and are preferable. Is an aromatic hydrocarbon group or an aliphatic hydrocarbon group.

Further, R1 to R23 can preferably include alkyl, benzyl, substituted benzyl, arylalkyl, substituted arylalkyl and the like, more preferably alkyl or benzyl, and further preferably benzyl.

The "substituted benzyls" include, for example, alkyl-substituted benzyls, respectively, and the "substituted arylalkyls" include, for example, alkyl-substituted arylalkyls, respectively. Be done. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The protecting groups for the phenolic hydroxyl groups of R1 to R23 may be the same or different from each other, but if they are the same, there is an advantage that the preparation thereof becomes easy.

X1 and X2 are any protecting groups selected from the groups used as protecting groups for alcoholic hydroxyl groups, which may be the same or different from each other. It is preferable that X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, arylalkyl groups or substituted arylalkyl groups, respectively.

In formula (I), Y is any protecting group selected from the groups used as the protecting group for the alcoholic hydroxyl group. As will be described later, the protecting group Y is a group that is eliminated during a reaction with another compound, and may be hereinafter referred to as a leaving group.

Preferred examples of the protecting group for the alcoholic hydroxyl group include acyl, substituted acyl, benzyl, substituted benzyl, alkyl, arylalkyl and substituted arylalkyl. Examples of the "acyl" include acyls of aliphatic carboxylic acids or aromatic carboxylic acids, respectively. Examples of the "substituted acyl" include acyl substituted with an aryl of an acyl of an aromatic carboxylic acid, specifically, an aryl (more specifically, for example, phenyl) is substituted with a substituent, for example, an alkyl. The acylation that was made is mentioned.

As for the substituted benzyl and the substituted arylalkyl, similarly to the protecting group of the phenolic hydroxyl group, examples of the "substituted benzyl" include, for example, a benzyl substituted with an alkyl, respectively, as the "substituted arylalkyl". Independently, for example, arylalkyl substituted with alkyl, for example. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The leaving group Y is a group that is eliminated during a reaction between the compound represented by the general formula (I) and the compound represented by the general formula (V-1) or (V-2). It is preferably an alkyloxy group, an alkyloxyalkyloxy group or an arylalkyloxy group.

The size of the alkyl group of the alkyloxy group is preferably 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms. More preferably, it is an alkyl having 1 to 5 carbon atoms. More preferably, it is methyl, ethyl, isopropyl, allyl and the like. Most preferably methyl.

The size of the alkyloxy group of the alkyloxyalkyloxy group is preferably 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms, respectively. A methoxymethoxy group or the like is preferable, and an ethylene glycol group is most preferable.

The size of the arylalkyloxy group is preferably 7 to 20 carbon atoms, and more preferably 7 to 10 carbon atoms. More preferably, it is phenylalkyl having 7 to 10 carbon atoms, and most preferably benzyl.

The reactive derivative of the epigallocatechin monomer used as the production raw material used in the production method according to the present embodiment is derived from any epigallocatechin as long as it corresponds to the above chemical formula, regardless of whether it is of natural origin or synthetic origin. It can be used even if it is a thing. Further, those synthesized by a known synthetic organic chemical method can also be used.

[Condensation reaction]
FIG. 1 shows the mechanism of the condensation reaction in the embodiment of the present invention. In FIG. 1, a Lewis acid first coordinates with an oxygen atom of an acetyl group and an alkoxyl group which is an electron requesting site, activates the alkoxy group and desorbs it. Next, the electrophile site is sterically activated by the involvement of the adjacent group of the acetyl group, and the 8-position of the electrophile with high electron density attacks the 4'-position of the electrophile to generate an oligomer. To.

[Deprotection process]
The production method according to the present embodiment deprotects the protecting group of the phenolic hydroxyl group and the protecting group of the alcoholic hydroxyl group of the compound represented by the general formula (VI) obtained in the first condensation step as an arbitrary step. This (hereinafter, also referred to as “deprotection step”) produces a compound represented by the general formula (VII). Here, in the general formula (VII), n, which is a repetition of the structure in parentheses, represents an integer of 1 or 2 or more.

The condensation is preferably carried out in the presence of a Lewis acid, and the Lewis acid used as a reaction catalyst in the method of the present invention is preferably zinc triflate (Zn (OTf) ₂ ) or ytterbium triflate (Yb (OTf) ₃ ). Further, ytterbium triflate (Yb (OTf) ₃ ) is preferable in the case of producing epigallocatechin 4, pentamer.

These reaction catalysts are available as commercially available reagents. The form of the reaction catalyst used is not particularly limited and may be in the powder state or in the crystallized state, but the powder state is preferable.

The amount of Lewis acid added as the reaction catalyst is not particularly limited, but the suitable amount to be used differs depending on the degree of polymerization. For example, in the production of catechin or epicatechin dimer, the amount of zinc triflate (Zn (OTf) ₂ ) added is preferably about 0.8 equivalent, and in the production of epigalocatechin tetramer, ytterbium trifurate. The amount of (Yb (OTf) ₃ ) added is preferably about 5.0 equivalents, and even in the case of a pentamer, it is preferably about 5.0 equivalents.

Further, in the production method according to the present embodiment, it is preferable that the ratio of the reactive derivatives of the two types of epigallocatechin oligomers, the electrophile and the nucleophile, to the production raw material is approximately 1: 1. When the conventional method for producing an epicatechin trimer is diverted to an epigallocatechin oligomer, for example, the method described in Non-Patent Document 4 uses a large excess of one of the production raw materials, for example, 1: 2 to 1: 4.5. Since it is used in the same amount, it is very inefficient and requires time and effort for purification treatment after the reaction. The production method according to the present embodiment is an extremely efficient method in which the ratio of the reactive derivative of the electrophile to the nucleophile is 1: 0.8 to 1.2, and the removal of the protecting group and the removal of the protecting group are performed. It can be said that the post-reaction treatment operation such as removal of the residual raw material is also an extremely simple method.

The compound represented by the general formula (I) used as a raw material for producing the first condensation step is obtained by introducing a substituent into the dimer of epigallocatechin. That is, (a) the protecting groups R1 to R10 are introduced into the phenolic hydroxyl group of the dimer of epigallocatekin, and if necessary, protected to the alcoholic hydroxyl group of the dimer of (b) epigallocatekin. It can be produced by introducing X1 and X2 of the groups and (c) introducing an ethylene glycol group or the like as the leaving group Y of the epigalocatechin-reactive derivative.

Specifically, an aliphatic or aromatic hydrocarbon group is introduced as R1 to R10 into the phenolic hydroxyl group of the dimer of epigallocatechin in step (a), and a benzyl group is more preferably introduced. do. The procedure for introducing the benzyl group can be carried out by first adding benzyl bromide to the monomer of epigallocatechin gallate, removing the gallate group by hydrolysis, and then dimerizing. The reaction with benzyl bromide can be preferably carried out, for example, by using dimethylformamide (hereinafter, also referred to as “DMF”) as a solvent.

The procedure for introducing an acetyl group as the protecting groups X1 and X2 into the alcoholic hydroxyl group in step (b) can be carried out, for example, by adding acetic anhydride and reacting. The addition of acetic anhydride can be carried out, for example, in pyridine as a solvent.

The introduction of the methoxy group in step (c) can be carried out, for example, by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (hereinafter, also referred to as "DDQ") and reacting with methanol. can. The introduction of the methoxy group can be carried out, for example, in dichloromethane as a solvent. Further, the introduction of an ethylene glycol group or the like is carried out, for example, by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (DDQ) and reacting with ethylene glycol in the same manner as the above-mentioned methoxy group. Can be done.

The compound represented by the chemical formula (V-1) or (V-2) in the first condensation step can be obtained, for example, by introducing a substituent into the monomer or oligomer of epigallocatechin. That is, the protecting groups R11 to R24 are introduced into the phenolic hydroxyl group of the monomer or oligomer of epigallocatechin.

The order of steps (a) to (c) is as follows: (a) introduction of R1 to R10 of the protecting group of the phenolic hydroxyl group → (b) introduction of X1 and X2 of the protecting group of the alcoholic hydroxyl group → (c) elimination. The order of introduction of the leaving group Y, or (a) introduction of R1 to R10 of the protecting group of the phenolic hydroxyl group → (c) introduction of the leaving group Y → (b) introduction of the protecting groups X1 and X2 of the alcoholic hydroxyl group. It is preferable to carry out in the order of.

The solvent used for the coupling reaction may be any solvent as long as it does not affect the reaction. For example, a solvent such as hexane, benzene, toluene, xylene, carbon tetrachloride, methylene chloride, chloroform, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dimethylformamide, acetonitrile, ethyl acetate, dimethylsulfoxide, etc., alone or Can be mixed and used. Among these solvents, benzene, hexane, toluene, xylene, carbon tetrachloride, and methylene chloride are preferable, and methylene chloride is most preferable.

The reaction time of the present invention is not particularly limited, and can be appropriately adjusted according to the type of the raw material to be produced and the type of the target product. If the reaction time is too short, the reaction may be insufficient and unreacted raw materials may remain, resulting in a decrease in product yield. In addition, if the reaction time is too long, not only the work efficiency deteriorates, but also the products or the products and the unreacted raw materials react irregularly to produce impurities other than the intended ones, and the reaction efficiency is rather lowered. There is. Specifically, in the case of producing a tetramer, about 19 hours is preferable.

A feature of the production method of the present invention is that the reaction temperature is not particularly limited. The conventional manufacturing method, for example, the method described in Non-Patent Document 1, requires a low temperature condition (for example, −20 ° C.), whereas the method of the present invention does not require such a low temperature condition. Further, the reaction temperature in the method of the present invention is not particularly limited and can be appropriately adjusted according to the type of the raw material to be produced and the type of the target product. Specifically, it is preferably room temperature or lower (0 ° C or higher and 23 ° C or lower). The lower limit is more preferably 10 ° C or higher, and particularly preferably 20 ° C or higher.

The ratio of the compound represented by the chemical formula (I) to the compound represented by the chemical formula (II) used in the first condensation step is preferably a composition close to a molar ratio of 1: 1 and 1: 0. It is preferable to react in an equal amount of 8.8 to 1.2. In this way, by making the addition ratio substantially the same, it is possible to prevent waste of excessive use of the raw material and further simplify the refining operation including removal of the residual raw material.

As a deprotecting method in the deprotecting step of the compound represented by the chemical formula (VI) of the deprotecting step, a known method can be used.

Specifically, for example, when an acetyl group is present as the protecting groups X1, X2, and Y of the alcoholic hydroxyl group, the acetyl group can be desorbed by a method of adding a tetrabutylammonium hydroxide or the like. As the solvent at this time, for example, tetrahydrofuran can be used.

Further, for example, when a benzyl group is present as all the protecting groups Rn of the phenolic hydroxyl group, the benzyl group is eliminated by a method of adding palladium hydroxide (Pd (OH) ₂ ) under a hydrogen atmosphere. be able to. As the solvent at this time, for example, a mixed solvent of tetrahydrofuran (THF), methanol, and water can be used.

As mentioned above, the invention has been described by embodiment, but the statements and drawings that form part of this disclosure should not be understood to limit the invention. This disclosure reveals to those skilled in the art various alternative embodiments, examples and operational techniques.

In the present embodiment, the compound of 4 or pentamer of epigallocatechin and the method for producing the same have been mainly described, but according to the present invention, a higher-order polymer of epigallocatechin can also be produced.

Such compounds are useful, for example, for identifying proanthocyanidin fractions in okra. Similar to conventional procyanidins, it can exhibit physiological effects such as antioxidant effect, antiviral effect, antibacterial effect, antitumor effect, arteriosclerosis inhibitory effect, gastric ulcer inhibitory effect, carcinogenesis inhibitory effect, hair growth activity effect, and whitening effect. It is expected and useful as a material for health foods and cosmetics.

Hereinafter, a second embodiment of the present invention will be described. In this embodiment, a compound of a trimer of epigallocatechin and a method for producing the same will be described.

[Compound]
The compound according to the second embodiment of the present invention is represented by, for example, the general formula (III).

In formula (III), R1 to R14 each independently represent an arbitrary protective group selected from the groups used as a protective group for a phenolic hydroxyl group, and X1 to X2 each independently represent an arbitrary protective group. Represents any protective group selected from the groups used as protective groups for alcoholic hydroxyl groups, where Z represents a hydroxyl group or hydrogen and the wavy bond represents a solid or broken wedge-shaped bond.

The production method according to the embodiment is, for example, a compound as an electrophile represented by the general formula (I) (in the general formula (I), R1 to R10 and X1 to X2 have the same meanings as described above). And the compound represented by the general formula (II) (in the general formula (II), the bonds represented by R11 to R14, Z and the wavy line have the same meanings as described above) and the compound represented by the general formula (II) are condensed (hereinafter, ". Also referred to as "first condensation step").

In the production method according to the present embodiment, the dimer of epigallocatechin represented by the general formula (I) is prepared as an electrophile, and the target product is produced in high yield at room temperature or lower without purification. can do. Specifically, when the dimer of epigallocatechin is made into an electrophile, the number of steps for synthesizing the trimer is compared with the case where the monomer of epigallocatechin is made into an electrophile, which is a conventional method. Is reduced to about 1/3, and the efficiency of synthesis is significantly improved. This is the first discovery by the present inventors.

In this production method, for example, the compound represented by the general formula (III) can be produced by the same method (first condensation step) as the step (FIG. 1) shown in the previous embodiment. That is, first, Lewis acid coordinates with the oxygen atom of the acetyl group and the alkoxyl group which is the electron requesting site, activates the alkoxy group and desorbs it. Next, the electrophile site is sterically activated by the involvement of the adjacent group of the acetyl group, and the 8-position of the electrophile with high electron density attacks the 4'-position of the electrophile to generate an oligomer. To. Here, the compound obtained in the first condensation step may further have a second condensation step in which the compound represented by the general formula (I) or (II) is further condensed. Further, the compounds obtained in the first condensation step may be condensed with each other. Therefore, the design of the compound represented by the general formula (III) becomes easy, and the production efficiency is also improved.

According to the production method according to the present embodiment, the homologous gas trimer containing epigallocatechin is not limited to the homologous gas trimer, and the epigallocatechin-containing heterogas trimer containing catechin or epicatechin as a part is also efficiently produced. Can be manufactured.

Also in the second embodiment, as in the previous embodiment, as an arbitrary step, the protecting group for the phenolic hydroxyl group and the alcoholic hydroxyl group of the compound represented by the general formula (III) obtained in the first condensation step can be used. By deprotecting the protecting group (deprotection step), a compound represented by the general formula (IV) (Z is a hydroxyl group or hydrogen, and the bond represented by a wavy line is a solid or broken wedge-shaped bond) is produced. ..

In addition, R1 to R14 are arbitrary protective groups selected from the groups used as protective groups for phenolic hydroxyl groups, which may be the same or different from each other, and are preferably aromatic hydrocarbon groups. Or it is an aliphatic hydrocarbon group.

Examples of R1 to R14 include alkyl, benzyl, substituted benzyl, arylalkyl, substituted arylalkyl and the like, more preferably alkyl or benzyl, and further preferably benzyl. The "substituted benzyls" include, for example, alkyl-substituted benzyls, respectively, and the "substituted arylalkyls" include, for example, alkyl-substituted arylalkyls, respectively. Be done. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The protecting groups for the phenolic hydroxyl groups of R1 to R14 may be the same or different from each other, but if they are the same, there is an advantage that the preparation thereof becomes easy.

X1 and X2 are hydrogen atoms or any protecting group selected from the groups used as protecting groups for alcoholic hydroxyl groups, which may be the same or different from each other. It is preferable that X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, arylalkyl groups or substituted arylalkyl groups, respectively.

Y is any protecting group selected as the leaving group from the groups used as the protecting group for the alcoholic hydroxyl group.

Preferred examples of the leaving group Y of the alcoholic hydroxyl group include acyl, substituted acyl, benzyl, substituted benzyl, alkyl, arylalkyl and substituted arylalkyl. Examples of the "acyl" include acyls of aliphatic carboxylic acids or aromatic carboxylic acids, respectively. Examples of the "substituted acyl" include acyl substituted with an aryl of an acyl of an aromatic carboxylic acid, specifically, an aryl (more specifically, for example, phenyl) is substituted with a substituent, for example, an alkyl. The acylation that was made is mentioned.

As for the substituted benzyl and the substituted arylalkyl, similarly to the protecting group of the phenolic hydroxyl group, examples of the "substituted benzyl" include, for example, a benzyl substituted with an alkyl, respectively, as the "substituted arylalkyl". Independently, for example, arylalkyl substituted with alkyl, for example. These alkyl substituents preferably have 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms.

The leaving group Y is a group that is eliminated during the reaction of the compound represented by the general formula (I) with the compound represented by the general formula (II), and is preferably an alkyloxy group or an alkyl. It is an oxyalkyloxy group or an arylalkyloxy group.

The size of the alkyl group of the alkyloxy group is preferably 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms. More preferably, it is an alkyl having 1 to 5 carbon atoms. More preferably, it is methyl, ethyl, isopropyl, allyl and the like. Most preferably methyl.

The size of the alkyloxy group of the alkyloxyalkyloxy group is preferably 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms, respectively. A methoxymethoxy group or the like is preferable, and an ethoxyethoxy group is most preferable.

The size of the arylalkyloxy group is preferably 7 to 20 carbon atoms, and more preferably 7 to 10 carbon atoms. More preferably, it is phenylalkyl having 7 to 10 carbon atoms, and most preferably benzyl.

Z represents hydrogen or a hydroxyl group.

The reactive derivative of the epigallocatechin monomer used as the production raw material used in the production method of the present invention is derived from any epigallocatechin as long as it corresponds to the above chemical formula, regardless of whether it is of natural origin or synthetic origin. It can be used even if it exists. Further, those synthesized by a known synthetic organic chemical method can also be used.

The condensation is preferably carried out in the presence of Lewis acid. As the Lewis acid used as a reaction catalyst in the method of the present invention, zinc triflate (Zn (OTf) ₂ ) and ytterbium triflate (Yb (OTf) ₃ ) are preferable. In particular, ytterbium triflate (Yb (OTf) ₃ ) is preferable for producing epigalocatechin trimers, and zinc triflate (Yb (OTf) 3) is preferable, and epigalocatechin-epicarocatechin-epicatechin or epigalocatechin-epicarocatechin-catechin (zinc triflate). Zn (OTf) ₂ ) is preferable.

These reaction catalysts are available as commercially available reagents. The form of the reaction catalyst used is not particularly limited and may be in the powder state or in the crystallized state, but the powder state is preferable.

The amount of Lewis acid added as a reaction catalyst is not particularly limited, but the suitable amount of catechin or epigallocatechin is different depending on the type and dimer. For example, in the production of catechin or epicatechin dimer, the amount of zinc triflate (Zn (OTf) ₂ ) added is preferably about 0.8 equivalent, and in the production of epigalocatechin trimerate, itterbium trifurate. The amount of (Yb (OTf) ₃ ) added is preferably about 2.0 equivalents, and in the case of epigalocacatechin-epigallocatechin-epicatechin or epigalocatecchin-epigallocatechin-catechin, zinc trifurate (Zn (OTf)). ) The addition amount of ₂ ) is preferably about 2.0 equivalent.

In the production method according to the second embodiment of the present invention, the ratio of the two epigallocatechin oligomer-reactive derivatives, the electrophile and the nucleophile, to the production raw materials is preferably about 1: 1. .. When the conventional production method for epicatechin trimers is diverted, for example, the method described in Non-Patent Document 1 uses a large excess of one production raw material, for example, 1: 3 equivalent, which is extremely inefficient. This is a method that requires time and effort for the purification process after the reaction. On the other hand, the production method according to the embodiment of the present invention is an extremely efficient method in which the ratio of the reactive derivative of the electrophile to the nucleophile is 1: 0.8 to 1.2, and it is protected. It can be said that post-reaction treatment operations such as removal of groups and removal of residual raw materials are also extremely simple methods.

The compound represented by the general formula (I) used as a raw material for producing the first condensation step can be obtained by introducing a substituent into the dimer of epigallocatechin. That is, (a) the protecting groups R1 to R10 are introduced into the phenolic hydroxyl group of the dimer of epigallocatekin, and if necessary, protected to the alcoholic hydroxyl group of the dimer of (b) epigallocatekin. It can be produced by introducing X1 and X2 of the groups and (c) introducing an ethoxyethoxy group (hereinafter, also referred to as "OEE") as Y of the epigallocatekin oligomer-reactive derivative.

Specifically, an aliphatic or aromatic hydrocarbon group is introduced as R1 to R10 into the phenolic hydroxyl group of the dimer of epigallocatechin in step (a), and a benzyl group is more preferably introduced. do. The procedure for introducing the benzyl group can be carried out by first adding benzyl bromide to the monomer with epigallocatechin galley, removing the gallate group by hydrolysis, and then dimerizing. The reaction with benzyl bromide can be preferably carried out, for example, by using dimethylformamide (hereinafter, also referred to as “DMF”) as a solvent.

The procedure for introducing an acetyl group as the protecting groups X1 and X2 into the alcoholic hydroxyl group in step (b) can be carried out, for example, by adding acetic anhydride and reacting. The addition of acetic anhydride can be carried out, for example, in pyridine as a solvent.

The introduction of the methoxy group in step (c) can be carried out, for example, by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (hereinafter, also referred to as "DDQ") and reacting with methanol. can. The introduction of the methoxy group can be carried out, for example, in dichloromethane as a solvent. Further, the introduction of the ethoxyethoxy group (OEE) is carried out by adding 2,3-dichloro-5,6-dicyano-para-benzoquinone (DDQ) and reacting with ethoxyethanol, for example, in the same manner as the above-mentioned methoxy group. Can be done by.

The compound represented by the chemical formula (II) in the first condensation step can be obtained, for example, by introducing a substituent into the monomer or oligomer of epigallocatechin. That is, the protecting groups R11 to R14 are introduced into the phenolic hydroxyl group of the monomer or oligomer of epigallocatechin.

The order of steps (a) to (c) is as follows: (a) introduction of R1 to R10 of the protecting group of the phenolic hydroxyl group → (b) introduction of X1 and X2 of the protecting group of the alcoholic hydroxyl group → (c) elimination. The order of introduction of the leaving group Y, or (a) introduction of R1 to R10 of the protecting group of the phenolic hydroxyl group → (c) introduction of the leaving group Y → (b) introduction of the protecting groups X1 and X2 of the alcoholic hydroxyl group. It is preferable to carry out in the order of.

The solvent used for the coupling reaction may be any solvent as long as it does not affect the reaction. For example, a solvent such as hexane, benzene, toluene, xylene, carbon tetrachloride, methylene chloride, chloroform, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, dimethylformamide, acetonitrile, ethyl acetate, dimethylsulfoxide, etc., alone or Can be mixed and used. Among these solvents, benzene, hexane, toluene, xylene, carbon tetrachloride, and methylene chloride are preferable, and methylene chloride is most preferable.

In the present embodiment, the reaction time of the invention is not particularly limited, and can be appropriately adjusted according to the type of the raw material to be produced and the type of the target product. If the reaction time is too short, the reaction may be insufficient and unreacted raw materials may remain, resulting in a decrease in product yield. In addition, if the reaction time is too long, not only the work efficiency deteriorates, but also the products or the products and the unreacted raw materials react irregularly, and impurities other than the intended ones are produced, and the reaction efficiency is rather lowered. In some cases. Specifically, in the case of producing a trimer, about 20 hours is preferable, as shown in the following examples.

Hereinafter, examples will be described, but the present invention is not limited to the following examples. First, the structural formulas of epigallocatechin 3, 4, and 5 in this example are summarized in FIG. 2 below. Hereinafter, in Adjustment Example 1, the synthesis of epigallocatechin trimeric condensate is performed, in Preparation Example 2, the synthesis of epigallocatechin-epigallocatechin-catechin, and in Preparation Example 3, epigalocatechin-epigalocatechin-epicatechin. Regarding the synthesis, in Preparation Example 4, the synthesis of epigalocacatechin tetramer condensate will be described, and in Preparation Example 5, the synthesis of epigallocatechin pentamer will be described together with comparative preparation examples.

[Preparation Example 1] Synthesis of Epigallocatechin Trimer Condensate First, an electrophile, which is a self-condensed dimer, is prepared in the system (in a flask). In Adjustment Example 1, a method for synthesizing a tetramer is used for convenience. (Described later), FIG. 3 will be diverted and described. In FIG. 3, an epigallocatechin derivative (dimer) prepared in three steps from epigallocatechin gallate (EGCG) represented by the general formula (a) is used as a production raw material and is represented by the general formula (b). A dimer like this is produced. The reaction was carried out at room temperature (20 ° C.) for 2 hours using 2.0 equivalents of Zn (OTf) ₂ as a reaction catalyst. Furthermore, the prepared product was activated with 2 equivalents of Yb (OTf) ₃ in one-pot without isolation and purification, and the nucleophile derived from epigallocatekin was used at room temperature (20 ° C) for 20 hours. The epigalocatechin trimer condensate was obtained in a yield of 51% in two steps.

表１より、反応触媒として２当量のＹｂ（ＯＴｆ）_３を用いることにより、収率が上ることが明らかになった。 (Comparative preparation example)
Epigalocatechin trimers were prepared under the same conditions as in Preparation Example 1 except that the reaction catalyst and the reaction time were changed to the following conditions. The changed conditions and the obtained results are summarized in Table 1 below.

From Table 1, it was clarified that the yield was improved by using 2 equivalents of Yb (OTf) ₃ as the reaction catalyst.

[Preparation Example 2] Synthesis of Epigallocatechin-Epigallocatechin-Catechin As in the case of Adjustment Example 1, epigallocatechin gallate (EGCG) represented by the general formula (a) was prepared in three steps. A self-condensed dimer is obtained by reacting a catechin derivative (monomer) as a production raw material and 2.0 equivalents of Zn (OTf) ₂ as a reaction catalyst at room temperature (20 ° C) for 2 hours. A catechin can be prepared in-system (in a flask). The prepared product is activated in one-pot with 2 equivalents of Zn (OTf) ₂ without isolation and purification, and reacted with a catechin-derived nucleophile at room temperature (20 ° C) for 20 hours. The epigalocatechin-epigalocatechin-catechin condensate was obtained in a yield of 47% in two steps.

[Comparative Preparation Example] Epigallocatechin-Epigallocatechin-Catechin Synthesis Epigallocatechin-epigallocatechin-catechin under the same conditions as in Preparation Example 2, except that the reaction catalyst and reaction time were changed to the following conditions. Was prepared. The changed conditions and the obtained results are summarized in Table 2 below.

[Preparation Example 3] Synthesis of Epigallocatechin-Epigallocatechin-Epicatechin As in the case of Adjustment Example 1, epigallocatechin gallate (EGCG) represented by the general formula (a) is prepared in three steps. A self-condensed dimer by using a gallocatechin derivative (monomer) as a production raw material and reacting it at room temperature (20 ° C) for 2 hours with 2.0 equivalents of Zn (OTf) ₂ as a reaction catalyst. Can be prepared in the system (in a flask). By activating this compound in one-pot with 2 equivalents of Yb (OTf) ₃ without isolation and purification, and reacting it with an epicatechin-derived nucleating agent at room temperature (20 ° C) for 20 hours. The epigallocatechin-epigallocatechin-epicatechin condensate was obtained in a yield of 42% in two steps.

[Preparation Example 4] Synthesis of Epigallocatechin Tetramer Condensate As shown in FIG. 3, an epigallocatechin derivative prepared in three steps from epigallocatechin gallate (EGCG) represented by the general formula (a). A self-condensed dimer is obtained by reacting (monomer) as a production raw material and 0.8 equivalents of Zn (OTf) ₂ as a reaction catalyst at room temperature (20 ° C) for 2 hours. Electronic bodies can be prepared. This compound is generally isolated and purified, activated with 5 equivalents of Yb (OTf) ₃ , and reacted with epigallocatechin-derived nucleophile (c) at room temperature (20 ° C) for 20 hours. The epigallocatechin tetramer condensate represented by the formula (d) was obtained in a yield of 45%.

表３より、反応触媒として５当量のＹｂ（ＯＴｆ）_３を用いることにより、収率が向上することが明らかになった。 [Comparative Preparation Example] Synthesis of Epigalocatechin Tetramer Epigalocacatechin tetramer was prepared under the same conditions as in Preparation Example 4 except that the reaction catalyst and the reaction time were changed to the following conditions. The changed conditions and the obtained results are summarized in Table 3 below.

From Table 3, it was clarified that the yield was improved by using 5 equivalents of Yb (OTf) ₃ as the reaction catalyst.

[Preparation Example 5] Synthesis of Epigallocatechin pentamer As shown in FIG. 4, an epigallocatechin derivative (1 amount) prepared in 3 steps from epigallocatechin gallate (EGCG) represented by the general formula (a). The body) is used as a raw material for production, and 0.8 equivalents of Zn (OTf) ₂ is used as a reaction catalyst to react at room temperature (20 ° C) for 2 hours to obtain a self-condensed dimer. Can be prepared. This compound is isolated and purified, activated with 5 equivalents of Yb (OTf) ₃ , and reacted with the epigallocatechin trimer nucleophile (e) at room temperature (20 ° C) for 20 hours. The epigalocatechin pentamer condensate represented by the general formula (f) was obtained in a yield of 30%.

[Comparative Preparation Example] Synthesis of Epigalocatechin pentamer Epigalocatechin pentamer was prepared under the same conditions as in Preparation Example 5, except that the reaction catalyst and the reaction time were changed to the following conditions. The changed conditions and the obtained results are summarized in the table below.

The examples of the present invention have been described above. A feature of the production method of the present invention is that the reaction temperature is not particularly limited. The conventional manufacturing method, for example, the method described in Non-Patent Document 1, requires a low temperature condition (for example, −20 ° C.), whereas the method of the present invention does not require such a low temperature condition. Further, the reaction temperature in the method of the present invention is not particularly limited and can be appropriately adjusted according to the type of the raw material to be produced and the type of the target product. Specifically, it is preferably room temperature or lower (0 ° C or higher and 23 ° C or lower). The lower limit is more preferably 10 ° C or higher, and particularly preferably 20 ° C or higher.

Further, in the case of producing a trimer, the ratio of the compound represented by the chemical formula (I) to the compound represented by the chemical formula (II) used in the first condensation step is close to the molar ratio of 1: 1. It is preferable to mix them, and it is preferable to react them in an equal amount of 1 to 0.8 to 1.2. In this way, by making the addition ratio substantially the same, it is possible to prevent waste of excessive use of the raw material and further simplify the refining operation including removal of the residual raw material.

Further, as a deprotecting method in the deprotecting step of the compound represented by the chemical formula (III) in the deprotecting step, a known method can be used. Specifically, for example, when an acetyl group is present as the protecting groups X1, X2, and Y of the alcoholic hydroxyl group, the acetyl group can be desorbed by a method of adding a tetrabutylammonium hydroxide or the like. can. As the solvent at this time, for example, tetrahydrofuran can be used.

Further, for example, when a benzyl group is present as the protecting groups R1 to R14 of the phenolic hydroxyl group, the benzyl group is removed by a method of adding palladium hydroxide (Pd (OH) ₂ ) under a hydrogen atmosphere. Can be separated. As the solvent at this time, for example, a mixed solvent of tetrahydrofuran (THF), methanol, and water can be used.

As mentioned above, the invention has been described by embodiment, but the statements and drawings that form part of this disclosure should not be understood to limit the invention. This disclosure reveals to those skilled in the art various alternative embodiments, examples and operational techniques.

In the embodiment of the present invention, the method for producing a homologous multimer of epigallocatechin has been mainly described, but according to the present invention, a hetero-gas oligomer containing epigallocatechin can also be produced.

Further, in the above embodiments and examples, the production method has been mainly described, but according to the present invention, the epigallocatechin multimer compound obtained by the above production method is, for example, a proanthocyanidin fraction in okra. It is useful for the identification of. Similar to conventional procyanidins, it can exhibit physiological effects such as antioxidant effect, antiviral effect, antibacterial effect, antitumor effect, arteriosclerosis inhibitory effect, gastric ulcer inhibitory effect, carcinogenesis inhibitory effect, hair growth activity effect, and whitening effect. It is expected and useful as a material for health foods and cosmetics.

According to the present invention, epigallocatechin oligomer can be easily produced in a high yield. Such oligomers are useful, for example, for the identification of prodelphinidins in okra. The oligomer produced by the present invention makes it easier to identify the biodelphinidins in the organism, which makes it easier to understand the bioactivity of each fraction. It is expected that the applications of prodelphinidins will be expanded. Furthermore, the clarification of the activity and related molecules will provide clues to elucidate the mechanism of action, and the development of more effective bioactive molecules can be expected from that mechanism.

Claims (17)

The following general formula (VI) (in the formula, R1 to R23 are arbitrary protecting groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcoholic properties. An arbitrary protecting group independently selected from the groups used as a protecting group for a hydroxyl group, Z is a hydroxyl group, and n is an integer of 1 or more and 10 or less).

The compound according to claim 1, wherein R1 to R23 are independently aromatic hydrocarbon groups or aliphatic hydrocarbon groups. The compound according to claim 1 or 2, wherein X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, allylalkyl groups or substituted allylalkyl groups, respectively. .. General formula (VI) (In the formula, R1 to R23 are arbitrary protecting groups or hydrogens independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcohols. A manufacturing method for producing an arbitrary protecting group independently selected from the groups used as a protecting group for a sex hydroxyl group, or a compound represented by hydrogen, Z is a hydroxyl group, and n is an integer of 1 or more and 10 or less). And
The following general formulas (I) (in the formula, R1 to R10 are arbitrary protective groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcoholic. A compound represented by an arbitrary protective group independently selected from the groups used as a protective group for a hydroxyl group, where Y is a desorbing group), is a zinc trifurate (Zn (OTf) 2) or an itterbium trifurate (Zn (OTf) ₂ ) or itterbium trifurate (. In the presence of Lewis acid, which is Yb (OTf) ₃ ), the following general formula (V-1) or (V-2) (in the formula, R11 to R24 are groups used as protective groups for phenolic hydroxyl groups). A production method comprising a step of condensing with a compound represented by any protective group independently selected from the above, n is an integer of 1 or more and 9 or less).

The production method according to claim 4 , wherein Y is an alkyloxy group, an alkyloxyalkyloxy group or an arylalkyloxy group. The production method according to claim 5 , wherein Y is ethylene glycol. The production method according to claim 4 , wherein the Lewis acid is ytterbium trifurate (Yb (OTf) ₃ ). The production method according to any one of claims 4 to 7 , wherein the condensation is carried out at 0 ° C. or higher and 23 ° C. or lower. The production method according to claim 4 , further comprising a reaction step of deprotecting the protecting groups represented by R1 to R24 and X1 to X2. In the following general formula (III) (in the formula, R1 to R14 are arbitrary protecting groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcoholic. Any protective group independently selected from the groups used as the protecting group for the hydroxyl group, the bond represented by the wavy line is a wedge-shaped bond represented by a solid line or a broken line, and Z is a compound represented by a hydroxyl group or hydrogen ). ..

The compound according to claim 10 , wherein R1 to R14 are independently aromatic hydrocarbon groups or aliphatic hydrocarbon groups. The compound according to claim 10 or 11 , wherein X1 and X2 are independently acyl groups, substituted acyl groups, benzyl groups, substituted benzyl groups, alkyl groups, allylalkyl groups or substituted allylalkyl groups, respectively. .. In the following general formula (III) (in the formula, R1 to R14 are arbitrary protecting groups or hydrogens independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcohols. Any protective group or hydrogen independently selected from the groups used as a protective group for a hydroxy hydroxyl group, a bond represented by a wavy line is a solid or broken wedge-shaped bond, and Z is a hydroxyl group or hydrogen). A method for producing the represented compound .
The following general formulas (I) (in the formula, R1 to R10 are arbitrary protective groups independently selected from the groups used as protective groups for phenolic hydroxyl groups, and X1 to X2 are alcoholic. A compound represented by an arbitrary protective group independently selected from the groups used as a protective group for a hydroxyl group, where Y is a desorbing group), is a zinc trifurate (Zn (OTf) 2) or an itterbium trifurate (Zn (OTf) ₂ ) or itterbium trifurate (. In the presence of Lewis acid, which is Yb (OTf) ₃ , the following general formula (II) (in the formulas, R11 to R14 are among the groups used as protective groups for phenolic hydroxyl groups) without isolation and purification. A production method comprising the steps of condensing with any protective group independently selected from, where Z is a hydroxyl group or hydrogen, and the bond represented by a wavy line is a compound represented by a solid or broken wedge-shaped bond).

The compound according to claim 13 , wherein Y is an alkyloxy group, an alkyloxyalkyloxy group or an arylalkyloxy group. The production method according to claim 19, wherein the Lewis acid is ytterbium trifurate (Yb (OTf) ₃ ). The production method according to any one of claims 13 to 15 , wherein the condensation is carried out at 0 ° C. or higher and 23 ° C. or lower. 13. The production method according to claim 13 , further comprising a reaction step of deprotecting the protecting groups represented by R1 to R14 and X1 to X2.

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