Method for producing gallate-type epicatechin polymer or gallate-type epigallocatechin polymer

Abstract

To provide a method for efficiently producing a gallate epicatechin polymer or a gallate epigallocatechin polymer.SOLUTION: This production method includes a step for subjecting two molecules of gallate epicatechin to self-condensation in the presence of Lewis acid.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a gallate-type epicatechin polymer or a gallate-type epigallocatechin polymer.

Background Art

[0002] Epicatechin gallate and epigallocatechin gallate are esters in which gallic acid is bonded to the 3-position of the flavan-3-ol of epicatechin and epigallocatechin, respectively, and are known to have a wide range of physiological activities including antioxidant action.

[0003] Procyanidin gallate, which is a dimer of epicatechin gallate, has attracted attention because it has important biological activities such as DNA polymerase inhibitory activity and antitumor activity (Non-Patent Document 1).

[0004] Conventionally, when synthesizing a dimer of epicatechin gallate from a monomer of epicatechin gallate, as shown below, an epicatechin gallate electrophile (ii) prepared from epicatechin (i) and an epicatechin gallate nucleophile (vi) were separately synthesized. When both were condensed in the presence of ytterbium triflate (Yb(OTf) 3 ), a dimer compound (iv) was obtained, but the yield remained at 22% (Non-Patent Document 1). All protecting groups of this compound were removed to synthesize a gallate-type epicatechin dimer (v). The disadvantages of this method are that the electrophile (ii) and the nucleophile (vi) must be prepared separately, and the yield of the condensation reaction between the two is low. Therefore, it cannot be said to be an efficient synthesis (Scheme A below).

[0005]

Chemical Formula

[0006] Regarding a gallate-type epigallocatechin polymer in which two or more epigallocatechin gallates are polymerized, no synthesis example has been reported.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] The problem to be solved by the present invention is to provide a method for more efficiently producing a gallate-type epicatechin polymer and a gallate-type epigallocatechin polymer.

Means for Solving the Problems

[0009] The present invention includes the embodiments described below.

[0010] Item 1. A method for producing a compound represented by the general formula (III), which comprises a step of self-condensing a compound represented by the general formula (II) of 2 molecules.

[0011]

Chemical Formula

[0012] (In formula (II), X 1 is hydrogen or OR 8 and R 1 to R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group)

[0013]

Chemical Formula

[0014] (In formula (III), X 1 , R 1 to R8 and A is the same as defined in formula (II) Item 2. The production method according to Item 1, wherein the yield of the compound represented by the general formula (III) is 70% or more. Item 3. The production method according to Item 1 or 2, wherein the step of self-condensing is carried out in the absence of the compound represented by the general formula (VI).

[0015]

Chemical formula

[0016] (In formula (VI), X 11 is hydrogen or OR 18 and R 11 ~R 18 each independently represents a protecting group for a phenolic hydroxyl group) Item 4. The compound represented by the general formula (III).

[0017]

Chemical formula

[0018] (In formula (III), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group) Item 5. A crude product containing the compound represented by the general formula (III), wherein the amount of the dimer compound represented by the general formula (III) in the crude product is 70% by mass or more.

[0019]

Chemical formula

[0020] (In formula (III), X 1 is hydrogen or OR 8 and R 1 ~R 8Each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group) The step of producing the compound represented by the general formula (III) by the production method according to any one of Items 1 to 3, The step of removing the protecting group for the alcoholic hydroxyl group at the 4-position of the compound represented by the general formula (III) to obtain a compound represented by the general formula (IV), The step of removing the protecting group for the phenolic hydroxyl group of the compound represented by the general formula (IV) to obtain a compound represented by the general formula (V), which includes a method for producing a compound represented by the formula (V).

[0021]

Chemical formula

[0022] (In the formula, X 1 is hydrogen or OR 8 and R 1 ~R 8 Each independently represents a protecting group for a phenolic hydroxyl group)

[0023]

Chemical formula

[0024] (In formula (V), Y 1 is hydrogen or OH) Item 7. A compound represented by formula (V-2).

[0025]

Chemical formula

[0026] The step of producing the compound represented by the general formula (III) by the production method according to any one of Items 1 to 3, The step of reacting the compound represented by the general formula (III) with the compound represented by the general formula (VII) in the presence of a Lewis acid to obtain a compound represented by the general formula (VIII),

[0027] [Chemical formula]

[0028] (In formula (VII), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group)

[0029] [Chemical formula]

[0030] (In formula (VIII), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and m is 2 to 5) A method for producing a compound represented by formula (IX), further comprising a step of deprotecting a protecting group from the compound represented by formula (VIII).

[0031] [Chemical formula]

[0032] (In formula (IX), Y 2 is hydrogen or OH, and m is 2 to 5) Item 9. A compound represented by formula (IX-2).

[0033] [Chemical formula]

[0034] (In formula (IX-2), m is 2 to 5) [Advantages of the Invention]

[0035] According to the production method of the present invention, the gallate-type epicatechin polymer and the gallate-type epigallocatechin polymer can be produced more efficiently.

Embodiments for Carrying Out the Invention

[0036] Hereinafter, preferred embodiments for carrying out the present invention will be described. The embodiments described below show examples of typical embodiments of the present invention, and the present invention is not limited thereto. According to some aspects of the present invention, there is provided a method for producing a compound represented by the general formula (III), which includes a step of self-condensing two molecules of the compound represented by the general formula (II).

[0037]

Chemical formula

[0038] (In the formula, X 1 is hydrogen or OR 8 , R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group)

[0039]

Chemical formula

[0040] (In the formula, X 1 , R 1 ~R 8 , and A are the same as those defined in formula (II). Specifically, X 1 is hydrogen or OR 8 , R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group) R 1 ~R 8is a protecting group for phenolic hydroxyl groups, which may be the same or different from each other, and is preferably an aromatic hydrocarbon group or an aliphatic hydrocarbon group. The aromatic hydrocarbon group is preferably arylalkyl, substituted arylalkyl, etc., and more preferably benzyl. The aliphatic hydrocarbon group is preferably alkyl. The substituent of the substituted arylalkyl is, for example, an alkyl group, and the carbon number of this alkyl substituent is preferably 1 to 20, more preferably 1 to 10.

[0041] A is a protecting group for alcoholic hydroxyl groups, and is preferably acyl, substituted acyl, alkyl, arylalkyl, or substituted arylalkyl.

[0042] Examples of "acyl" include acyls of aliphatic carboxylic acids or aromatic carboxylic acids.

[0043] Examples of "substituted acyl" include acyls in which the aryl of the acyl of aromatic carboxylic acids is substituted, specifically, acyls in which phenyl is substituted with alkyl.

[0044] "Alkyl" preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl and its isomers, n-hexyl and its isomers, n-pentyl and its isomers, n-octyl and its isomers, n-nonyl and its isomers, n-decyl and its isomers, and is preferably methyl.

[0045] "Arylalkyl" preferably has 7 to 20 carbon atoms. Examples of arylalkyl include benzyl, phenethyl, diphenylmethyl, triphenylmethyl, styryl, cinnamyl, etc., and is preferably benzyl.

[0046] "Substituted arylalkyl", like the protecting group for phenolic hydroxyl groups, examples of "substituted arylalkyl" include arylalkyl substituted with alkyl, respectively. This alkyl substituent preferably has 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms.

[0047] The condensation is preferably carried out in the presence of a Lewis acid. 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 ). In general formula (II), when X 1 is hydrogen, the Lewis acid is preferably ytterbium triflate. In general formula (II), when X 1 is OR 8 , the Lewis acid is preferably zinc triflate. These reaction catalysts are available as commercially available reagents. The form of the reaction catalyst used is not particularly limited, and it may be in a powdered state or a crystallized state, but a powdered state is preferred.

[0048] The addition amount of the Lewis acid used as a reaction catalyst is not particularly limited, but in the production of gallate-type epicatechin dimers and gallate-type epigallocatechin dimers, the addition amount of zinc triflate is preferably about 0.7 to 1.0 equivalent, and the addition amount of ytterbium triflate is preferably about 0.7 to 3.0 equivalent, based on 1 equivalent of the compound represented by general formula (II).

[0049] The electrophile prepared from epicatechin gallate represented by general formula (II) is known (see, for example, Suda, M. et al., Bioorg. Med. Chem. Lett. 2013, 23, 4935 - 4939), and those skilled in the art can synthesize it by ordinary organic synthetic chemical methods.

[0050] Instead, the electrophile prepared from epicatechin gallate or epigallocatechin gallate represented by the general formula (II) can also be produced by introducing a substituent into epicatechin or epigallocatechin. For this method, see, for example, Bioorganic & Medicinal Chemistry 13(8), 2005, 2759-2771. Specifically, it consists of procedure (1) an ester bond between epicatechin or epigallocatechin and gallic acid, procedure (2) introduction of a protecting group to the phenolic hydroxyl group, and procedure (3) introduction of an OA group (OEE) to the 4-position.

[0051] Previously, the inventors succeeded in synthesizing an epicatechin dimer by self-condensation of two molecules of an electrophile of epicatechin that is not of the gallate type, followed by removal of the protecting group (Suda, M. et al., Synthesis 2014, 46, 3351-3355). In this self-condensation, ytterbium triflate (Yb(OTf) 3 ) and zinc triflate (Zn(OTf) 2 ) were used as Lewis acids. However, when the same epicatechin was polymerized with the same equivalent of Lewis acid, the yield of the dimer was higher with zinc triflate than with ytterbium triflate. At most, the yield of the dimer was 58% with 0.8 equivalents of zinc triflate.

[0052] Epicatechin gallate and epigallocatechin gallate are expected to be more bulky and more difficult to self-condense because gallic acid is bonded to the 3-position of the flavan-3-ol of epicatechin and epigallocatechin, compared with epicatechin and epigallocatechin.

[0053] However, surprisingly, from the monomers of the gallate-type epicatechin protectant represented by the general formula (II), in the presence of ytterbium triflate, the compound represented by the general formula (III) could be prepared in a high yield of 74% by self-condensation. Unexpectedly, in the self-condensation of the monomers of the gallate-type epicatechin protectant, a higher yield was obtained when ytterbium triflate was used as the Lewis acid than zinc triflate (the yield with zinc triflate was about 51%).

[0054] Hereinafter, the yield of the compound represented by the general formula (III) means the ratio of the amount of the compound represented by the general formula (III) produced by the self-condensation of the monomers to the total amount of the monomers of the gallate-type epicatechin protectant or the gallate-type epigallocatechin protectant represented by the general formula (II).

[0055] In some preferred embodiments, in the method for producing the compound represented by the general formula (III) described above, the yield of the compound represented by the general formula (III) is 70% or more.

[0056] In some preferred embodiments, the step of performing the self-condensation is carried out in the absence of the compound represented by the general formula (VI).

[0057] [Chemical formula]

[0058] (In the formula, X 11 is hydrogen or OR 18 and R 11 ~R 18 each independently represents a protecting group for a phenolic hydroxyl group) R 11 ~R 18is a protecting group for phenolic hydroxyl groups, which may be the same or different from each other, and is preferably an aromatic hydrocarbon group or an aliphatic hydrocarbon group. The aromatic hydrocarbon group is preferably arylalkyl, substituted arylalkyl, etc., and more preferably benzyl. The aliphatic hydrocarbon group is preferably alkyl. The substituent of the substituted arylalkyl is, for example, an alkyl group, and the number of carbon atoms of this alkyl substituent is preferably 1 to 20, and more preferably 1 to 10.

[0059] X in the compound represented by the general formula (II) 1 and X in the compound represented by the general formula (VI) 11 , R in the compound represented by the general formula (II) 1 ~R 8 and R in the compound represented by the general formula (VI) 11 ~R 18 are preferably the same. That is, when the compound represented by the general formula (II) is self-condensed, it is preferable that there is no compound represented by the general formula (VI) that does not have an OA group at the 4-position of flavan-3-ol in the compound represented by the general formula (II) in order to promote the self-condensation of the compound represented by the general formula (II).

[0060] According to some aspects of the present invention, a compound represented by the general formula (III) is provided.

[0061]

Chemical formula

[0062] (In the formula, X 1 is hydrogen or OR 8 , and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group) X 1 , R 1 ~R 8 , and the details of A are as described above for the compound represented by the general formula (III).

[0063] The compound represented by the formula (III) is a dimer of a gallate-type epicatechin protected form or a gallate-type epigallocatechin protected form, which is produced by self-condensation of monomers of the gallate-type epicatechin protected form or the gallate-type epigallocatechin protected form represented by the general formula (II). It is advantageous in that a dimer or a larger multimer of gallate-type epicatechin or gallate-type epigallocatechin can be efficiently produced using this compound.

[0064] According to some aspects of the present invention, there is provided a crude product containing a compound represented by the general formula (III), wherein the amount of the dimer compound represented by the general formula (III) in the crude product is 70% by mass or more.

[0065]

Chemical formula

[0066] (In the formula, X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group) X 1 , R 1 ~R 8 , and the details of A are as described above for the compound represented by the general formula (III).

[0067] Since the crude product containing the compound represented by the above formula (III) contains the compound represented by the formula (III) in a high content, it is advantageous in that a dimer or a larger multimer of gallate-type epicatechin or gallate-type epigallocatechin can be efficiently produced by purifying and using this crude product.

[0068] Purification of the compound represented by formula (III) from the crude product containing the compound represented by formula (III) generated after the step of self-condensing the compound represented by the general formula (II) of 2 molecules can be carried out by a known method such as chromatography using an appropriate stationary phase or packing material and an appropriate solvent.

[0069] In some embodiments, purification of the compound represented by formula (III) is carried out by silica gel column chromatography or preparative thin layer silica gel chromatography. Examples of the developing solvent and the eluting solvent include hexane, ethyl acetate, dichloromethane, chloroform, methanol, a mixed solvent of hexane and ethyl acetate, a mixed solvent of hexane and dichloromethane, a mixed solvent of hexane, ethyl acetate and dichloromethane, a mixed solvent of chloroform and methanol, a mixed solvent of acetic acid and acetonitrile, etc., but are not limited thereto. In a preferred embodiment, the purification is carried out by preparative thin layer silica gel chromatography, and the developing solvent is a mixed solvent of hexane, ethyl acetate and dichloromethane.

[0070] According to some aspects of the present invention, a method for producing a compound represented by formula (V) includes a step of producing a compound represented by general formula (III) by the production method described in any of the above, a step of removing the protecting group of the alcoholic hydroxyl group at the 4-position of the compound represented by general formula (III) to obtain a compound represented by general formula (IV), and a step of removing the protecting group of the phenolic hydroxyl group of the compound represented by general formula (IV) to obtain a compound represented by general formula (V).

[0071]

Chemical formula

[0072] (In the formula, X 1 is hydrogen or OR 8 and R 1 ~ R 8 each independently represents a protecting group for a phenolic hydroxyl group)

[0073] [Chemical formula]

[0074] (wherein Y 1 is hydrogen or OH) X in formula (III) 1 , R 1 ~R 8 , and the details of A are as described above for the compound represented by general formula (III). Further, when X 1 in formula (III) is hydrogen, Y 1 in formula (V) is hydrogen, and when X 1 in formula (III) is OR 8 , Y 1 in formula (V) is OH.

[0075] According to the above production method, a dimer of a gallate-type epicatechin protected form or a gallate-type epigallocatechin protected form produced by self-condensation can be used to efficiently produce a dimer of gallate-type epicatechin or gallate-type epigallocatechin.

[0076] The step of removing the protecting group of the alcoholic hydroxyl group at the 4-position of the compound represented by general formula (III) and the step of removing the protecting group of the phenolic hydroxyl group of the compound represented by general formula (IV) are both called deprotection steps.

[0077] In the deprotection steps of the compound represented by general formula (III) and the compound represented by general formula (IV), known methods can be used as the deprotection method.

[0078] Specifically, for example, when an acetyl group is present as the protecting group A of the alcoholic hydroxyl group, the acetyl group can be eliminated by a method such as adding sodium methoxide. As the solvent in this case, for example, methanol can be used. For the removal of the ethoxyethyl group, refer to Synthesis 2016, 48, 1525-1532.

[0079] Also, for example, when a benzyl group is present as the protecting group R of the phenolic hydroxyl group 1 ~R 8 the benzyl group can be eliminated by a method such as adding palladium hydroxide (Pd(OH) 2 ) under a hydrogen atmosphere. As the solvent in this case, for example, a mixed solvent of tetrahydrofuran (THF), methanol, and water can be used.

[0080] In some embodiments, the purification of the compound represented by the general formula (IV) and the compound represented by the general formula (V) is performed by silica gel column chromatography or preparative thin-layer silica gel chromatography. Examples of the developing solvent and the eluting solvent include hexane, ethyl acetate, dichloromethane, chloroform, methanol, a mixed solvent of hexane and ethyl acetate, a mixed solvent of hexane and dichloromethane, a mixed solvent of hexane, ethyl acetate, and dichloromethane, a mixed solvent of chloroform and methanol, etc., but are not limited thereto. In a preferred embodiment, the purification is performed by preparative thin-layer silica gel chromatography, and the developing solvent is a mixed solvent of hexane, ethyl acetate, and dichloromethane.

[0081] According to some aspects of the present invention, a compound represented by the formula (V-2) is provided.

[0082]

Chemical formula

[0083] By using the self-condensation of the monomers of the gallate-type epigallocatechin protectant of the present disclosure, the gallate-type epicatechin dimer, which is a compound represented by the formula (V-2), can be efficiently produced.

[0084] The gallate-type epicatechin dimer is known to have excessive cytokine production inhibitory activity and antiviral activity.

[0085] This gallate-type epicatechin dimer is expected to exhibit various physiological activities such as antioxidant activity, similar to other proanthocyanidins such as non-gallate-type epicatechin dimers and gallate-type epigallocatechin dimers, and is useful in fields such as food, medicine, and cosmetics.

[0086] According to some aspects of the present invention, by the above production method, a step of producing a compound represented by the general formula (III), and reacting the compound represented by the general formula (III) with a compound represented by the general formula (VII) to obtain a compound represented by the general formula (VIII),

[0087]

Chemical formula

[0088] (In the formula, X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group)

[0089]

Chemical formula

[0090] (In the formula, X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and m is 2 to 5) There is provided a method for producing a compound represented by the formula (IX), further including a step of removing the protecting group for the phenolic hydroxyl group from the compound represented by the general formula (VIII).

[0091]

Chemical formula

[0092] (In the formula, Y 2is hydrogen or OH, and m is from 2 to 5) X in formulas (VII) and (VIII) 1 and R 1 ~R 8 For the details of ~R, it is the same as that described above for X 1 , and R 1 ~R 8 in the compound represented by general formula (III). Also, when X 1 in formula (III) is hydrogen, X 1 in formulas (VII) and (VIII) is hydrogen, Y 1 in formula (IX) is hydrogen, and X 1 in formula (III) is OR 8 , then X 1 in formulas (VII) and 8(VIII) is OR 8 , and Y 1 in formula (IX) is OH.

[0093] The compound represented by general formula (VII) is a compound in which no protecting group is attached to the 4-position of the flavan-3-ol of gallate-type epicatechin or gallate-type epigallocatechin, compared with the compound represented by general formula (II), and acts as a nucleophile. X 1 and R 1 ~R 8 in the compound represented by general formula (II) and X 1 and R 1 ~R 8 in the compound represented by general formula (VII) are identical.

[0094] The step of reacting the compound represented by general formula (III) with the compound represented by general formula (VII) is preferably carried out in the presence of a Lewis acid. The Lewis acid used as a reaction catalyst is preferably zinc triflate (Zn(OTf) 2 ) or ytterbium triflate (Yb(OTf) 3 ). These reaction catalysts are available as commercially available reagents.

[0095] The solvent used in the step of reacting the compound represented by the general formula (III) with the compound represented by the general formula (VII) may be any solvent that does not affect the reaction. For example, solvents 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, and dimethyl sulfoxide can be used alone or in combination.

[0096] The reaction time in the step of reacting the compound represented by the general formula (III) with the compound represented by the general formula (VII) is not particularly limited and can be appropriately adjusted according to the types of production raw materials and the types of target products. For example, 5 to 24 hours can be mentioned, but it is not limited thereto.

[0097] The reaction temperature in the step of reacting the compound represented by the general formula (III) with the compound represented by the general formula (VII) is not particularly limited and can be appropriately adjusted according to the types of production raw materials and the types of target products. For example, it is preferably at or below room temperature (0 °C or higher and 23 °C or lower), but it is not limited thereto.

[0098] The step of removing the protecting group of the phenolic hydroxyl group from the compound represented by the general formula (VIII) can be carried out in the same manner as the step of removing the protecting group of the phenolic hydroxyl group of the compound represented by the general formula (III).

[0099] For example, when the protecting group R 1 ~R 8 of the phenolic hydroxyl group is a benzyl group, the benzyl group can be eliminated by a method such as adding palladium hydroxide (Pd(OH) 2 ) in a hydrogen atmosphere. As the solvent at this time, for example, a mixed solvent of tetrahydrofuran (THF), methanol, and water can be used.

[0100] The compound represented by formula (III) is a dimer of a gallate-type epicatechin protected form or a gallate-type epigallocatechin protected form, which is produced by self-condensation of monomers of the gallate-type epicatechin protected form or the gallate-type epigallocatechin protected form represented by general formula (II). It is advantageous in that trimers or higher gallate-type epicatechins or gallate-type epigallocatechin multimers can be efficiently produced using this compound.

[0101] The medium molecular weight gallate-type epicatechin or epigallocatechin polymer represented by formula (XI) obtained by the above production method is expected to exhibit antitumor, antiviral, anti-inflammatory activities including antioxidant activity, similar to non-gallate-type epicatechin multimers and epigallocatechin multimers, and is useful in fields such as food, medicine, and cosmetics.

[0102] According to some aspects of the present invention, a compound represented by formula (IX-2) is provided.

[0103]

Chemical formula

[0104] (In the formula, m is 2 to 5) The compound represented by formula (IX-2) is a gallate-type epigallocatechin multimer among the compounds represented by formula (IX), with monomer units being gallate-type epigallocatechin.

[0105] The present invention will be described more specifically with reference to the following examples, but the present invention is not limited thereto.

Examples

[0106] Example 1 Synthesis of Gallate-Type Epicatechin Dimer When the epicatechin gallate derivative (2) prepared in three steps from epicatechin (1) was treated with ytterbium triflate, the dimer (3) formed by the self-condensation of (2) (Suda, M. et al., Synthesis 2014, 46, 3351-3355) could be prepared in a yield of 74%. When the ethoxyethyl (OEE) group at the 4-position of this compound (3) was reductively removed using triethylsilane in the presence of a Lewis acid, compound (4) was obtained in a yield of 70%. All the protecting groups of this compound (4) were removed (Ichikawa, M. et al., Synthesis 2016, 48, 1525-1532) to synthesize the gallate-type epicatechin dimer (5). The purification of compounds (3), (4), and (5) was carried out by preparative thin-layer silica gel chromatography, and the developing solvent was a mixed solvent of hexane, ethyl acetate, and dichloromethane (mass ratio hexane:ethyl acetate:dichloromethane = 10:1:5). The total yield from compound (2) was 52%, and an efficient new synthetic route was developed (Scheme 1).

[0107] [Chemical formula]

[0108] Example 2 Synthesis of Medium-Molecular Gallate-Type Epicatechin Polymer The compound (3) obtained by self-condensation reacts with the gallate-type epicatechin protecting group (7) using the reaction catalyst Zn(OTf), which is a Lewis acid, to form a 3- to 5-mer condensate (8). By deprotecting this compound, a 3- to 5-mer compound (9) of gallate-type epicatechin is produced. 2

[0109] [Chemical formula]

[0110] Example 3 Synthesis of Gallate-Type Epigallocatechin Dimer ​When the epigallocatechin gallate derivative (12) prepared in three steps from epigallocatechin gallate (11) is treated with zinc triflate, the dimer (13) formed by the self-condensation of the epigallocatechin gallate derivative (12) (Suda, M. et al., Synthesis 2014, 46, 3351-3355) can be prepared in a yield of 48%. After methylating the hydroxyl group of the ethylene glycol group at the 4-position of this compound (13) and then reductively removing it using triethylsilane in the presence of a Lewis acid, the compound (14) was obtained in a yield of 50%. All the protecting groups of this compound (14) were removed (Ichikawa, M. et al., Synthesis 2016, 48, 1525-1532), and the gallate-type epigallocatechin dimer (15) was synthesized (Scheme 3).

[0111]

Chemical Structure

Claims

1. A method for producing a compound represented by general formula (III), comprising a step of self-condensing two molecules of a compound represented by general formula (II) using ytterbium triflate or zinc triflate as a catalyst. 【Chemistry 1】 (In formula (II), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group. 【Chemistry 2】 (In formula (III), X 1 , R 1 ~R 8 and OA is as defined in formula (II).

2. 2. The process according to claim 1, wherein the yield of the compound represented by formula (III) is 70% or more.

3. The method according to claim 1 or 2, wherein the self-condensation step is carried out in the absence of a compound represented by general formula (VI). 【Chemistry 3】 (In formula (VI), 11 is hydrogen or OR 18 and R 11 ~R 18 each independently represents a protecting group for a phenolic hydroxyl group.

4. A compound represented by general formula (III): 【Chemistry 4】 (In formula (III), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group.

5. A crude product comprising a compound represented by general formula (III), wherein the amount of the dimeric compound represented by general formula (III) in the crude product is 70 mass% or more. 【Chemistry 5】 (In formula (III), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group.

6. A step of producing a compound represented by the general formula (III) by the production method according to any one of claims 1 to 3; a step of reductively deprotecting the ethoxyethyl group or the ethylene glycol group of the compound represented by general formula (III) using triethylsilane in the presence of a Lewis acid to obtain a compound represented by general formula (IV); and removing the protecting group of the phenolic hydroxyl group of the compound represented by general formula (IV) to obtain a compound represented by general formula (V). 【Chemistry 6】 (In the formula, X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group. 【Chemistry 7】 (In formula (V), Y 1 is hydrogen or OH)

7. A step of producing a compound represented by the general formula (III) by the production method according to any one of claims 1 to 3; A step of reacting a compound represented by general formula (III) with a compound represented by general formula (VII) in the presence of a Lewis acid to obtain a compound represented by general formula (VIII); 【Chemistry 8】 (In formula (VII), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group. 【Chemistry 9】 (In formula (VIII), X 1 is hydrogen or OR 8 and R 1 ~R 8 each independently represents a protecting group for a phenolic hydroxyl group, and m is 1 to 4. A method for producing a compound represented by formula (IX), further comprising a step of deprotecting the protecting group from the compound represented by general formula (VIII). 【Chemistry 10】 (In formula (IX), Y 2 is hydrogen or OH, and m is 1 to 4.

8. A compound represented by formula (IX-2). 【Chemistry 11】 (In formula (IX-2), m is 2 to 4.)

Images