JP7679064B2 - Method for producing gallate-type epicatechin polymer or gallate-type epigallocatechin polymer - Google Patents

Description

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

Epicatechin gallate and epigallocatechin gallate are esters in which gallic acid is bound 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 effects.

Procyanidin gallate, a dimer of epicatechin gallate, has been attracting attention due to its important biological activities, such as DNA polymerase inhibitory activity and antitumor activity (Non-Patent Document 1).

Conventionally, when synthesizing an epicatechin gallate dimer from an epicatechin gallate monomer, the epicatechin gallate electrophile (ii) and epicatechin gallate nucleophile (vi) prepared from epicatechin (i) were separately synthesized as shown below. When the two were condensed in the presence of ytterbium triflate (Yb(OTf) ₃ ), a dimer compound (iv) was obtained, but the yield was only 22% (Non-Patent Document 1). All protecting groups of this compound were removed to synthesize a gallate-type epicatechin dimer (v). The disadvantage of this method is 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 was not an efficient synthesis (see Scheme A below).

There have been no reported synthesis examples of gallate-type epigallocatechin polymers in which two or more epigallocatechin gallates are polymerized.

Suda, M. et al., Bioorg. Med. Chem. Lett. 2013, 23, 4935-4939

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

The present invention includes the following embodiments:

Item 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).

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

(In formula (III), X ₁ , R ₁ to R ₈ , and A are the same as defined in formula (II)).
Item 2. The method according to item 1, wherein the yield of the compound represented by formula (III) is 70% or more.
Item 3. The method according to item 1 or 2, wherein the self-condensation step is carried out in the absence of a compound represented by general formula (VI).

(In formula (VI), X ₁₁ is hydrogen or OR ₁₈ , and R ₁₁ to R ₁₈ each independently represent a protecting group for a phenolic hydroxyl group.)
Item 4. A compound represented by general formula (III):

(In formula (III), X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent 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 a compound represented by general formula (III), wherein the amount of the dimer compound represented by general formula (III) in the crude product is 70 mass% or more.

(In formula (III), X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group.)
Item 6. A process for producing a compound represented by the general formula (III) by the process according to any one of items 1 to 3;
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 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).

(wherein X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group).

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

Item 8. A process for producing a compound represented by the general formula (III) by the process according to any one of items 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);

(In formula (VII), X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group.)

(In formula (VIII), _X1 is hydrogen or _OR8 , _R1 to _R8 each independently represent a protecting group for a phenolic hydroxyl group, and m is an integer of 2 to 5.)
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).

(In formula (IX), _Y2 is hydrogen or OH, and m is 2 to 5.)
Item 9. A compound represented by formula (IX-2).

(In formula (IX-2), m is 2 to 5)

The manufacturing method of the present invention allows for more efficient production of gallate-type epicatechin polymers and gallate-type epigallocatechin polymers.

Preferred embodiments for carrying out the present invention will be described below. The embodiments described below are representative examples 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 general formula (III), comprising a step of self-condensing two molecules of a compound represented by general formula (II).

(wherein X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group).

(wherein X ₁ , R ₁ to R ₈ , and A are the same as defined in formula (II). Specifically, X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group.)
R ₁ to R ₈ may be the same or different and are protective groups for phenolic hydroxyl groups, preferably aromatic hydrocarbon groups or aliphatic hydrocarbon groups. The aromatic hydrocarbon group is preferably an aryl alkyl, a substituted aryl alkyl, or the like, more preferably benzyl. The aliphatic hydrocarbon group is preferably an alkyl. The substituent of the substituted aryl alkyl is, for example, an alkyl group, and the number of carbon atoms in this alkyl substituent is preferably 1 to 20, more preferably 1 to 10.

A is a protecting group for an alcoholic hydroxyl group, preferably acyl, substituted acyl, alkyl, arylalkyl, or substituted arylalkyl.

"Acyl" includes acyl of an aliphatic carboxylic acid or an aromatic carboxylic acid.

"Substituted acyls" include acyls in which the aryl of the acyl of an aromatic carboxylic acid is substituted, specifically acyls in which the phenyl is substituted with an alkyl.

"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, and n-decyl and its isomers, and is preferably methyl.

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

As with the protecting group for a phenolic hydroxyl group, the "substituted arylalkyl" includes, for example, an arylalkyl substituted with an alkyl. The alkyl substituent preferably has 1 to 20 carbon atoms, and more preferably has 1 to 10 carbon atoms.

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 the general formula (II), when _X1 is hydrogen, the Lewis acid is preferably ytterbium triflate. In the general formula (II), when _X1 is _OR8 , 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 may be in a powdered state or a crystallized state, but is preferably in a powdered state.

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

The electrophiles prepared from epicatechin gallate represented by general formula (II) are known (see, for example, Suda, M. et al., Bioorg. Med. Chem. Lett. 2013, 23, 4935-4939) and can be synthesized by those skilled in the art using conventional organic synthetic chemistry methods.

Alternatively, electrophiles prepared from epicatechin gallate or epigallocatechin gallate represented by 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, the method comprises step (1) ester bonding of epicatechin or epigallocatechin with gallic acid, step (2) introduction of a protecting group to the phenolic hydroxyl group, and step (3) introduction of an OA group (OEE) to the 4-position.

The inventors previously succeeded in synthesizing an epicatechin dimer by the self-condensation of two molecules of an electrophilic epicatechin that is not a gallate type, followed by the 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, and when the same epicatechin was polymerized with the same Lewis acid equivalent, the yield of the dimer was higher with zinc triflate than with ytterbium triflate, with the highest dimer yield being 58% with 0.8 equivalents of zinc triflate.

Compared to epicatechin and epigallocatechin, epicatechin gallate and epigallocatechin gallate are bulkier molecules because gallic acid is bonded to the 3-position of the flavan-3-ol of epicatechin and epigallocatechin, and it was predicted that self-condensation would be more difficult.

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

Hereinafter, the yield of the compound represented by general formula (III) is the ratio of the amount of the compound represented by general formula (III) produced by self-condensation of the monomer to the total amount of the monomer of the gallate-type epicatechin protected product or gallate-type epigallocatechin protected product represented by general formula (II).

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

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

(wherein X ₁₁ is hydrogen or OR ₁₈ , and R ₁₁ to R ₁₈ each independently represent a protecting group for a phenolic hydroxyl group).
R ₁₁ to R ₁₈ may be the same or different and are protective groups for phenolic hydroxyl groups, preferably aromatic hydrocarbon groups or aliphatic hydrocarbon groups. The aromatic hydrocarbon group is preferably an aryl alkyl, a substituted aryl alkyl, or the like, more preferably benzyl. The aliphatic hydrocarbon group is preferably an alkyl. The substituent of the substituted aryl alkyl is, for example, an alkyl group, and the number of carbon atoms in this alkyl substituent is preferably 1 to 20, more preferably 1 to 10.

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

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

(wherein X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group).
The details of X ₁ , R ₁ to R ₈ and A are as explained above with respect to the compound represented by formula (III).

The compound represented by formula (III) is a dimer of a protected epicatechin or a protected epigallocatechin of a gallate type produced by self-condensation of a monomer of a protected epicatechin or a protected epigallocatechin of a gallate type represented by general formula (II). This compound is advantageous in that it can be used to efficiently produce a gallate epicatechin or a gallate epigallocatechin dimer or a larger multimer of gallate epicatechin or gallate epigallocatechin.

According to some embodiments of the present invention, there is provided a crude product comprising a compound represented by general formula (III), in which the amount of the dimeric compound represented by general formula (III) in the crude product is 70 mass% or more.

(wherein X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and A represents a protecting group for an alcoholic hydroxyl group).
The details of X ₁ , R ₁ to R ₈ and A are as explained above with respect to the compound represented by formula (III).

The crude product containing the compound represented by formula (III) above is advantageous in that it contains a high content of the compound represented by formula (III) and can be purified and used to efficiently produce gallated epicatechin or gallated epigallocatechin dimers or larger gallated epicatechin or gallated epigallocatechin multimers.

The purification of the compound represented by formula (III) from the crude product containing the compound represented by formula (III) produced after the step of self-condensing two molecules of the compound represented by general formula (II) can be carried out by a known method such as chromatography using a suitable stationary phase or packing material and a suitable solvent.

In some embodiments, the compound represented by formula (III) is purified by silica gel column chromatography or preparative thin-layer silica gel chromatography. Examples of the developing solvent and elution solvent include, but are not limited to, hexane, ethyl acetate, dichloromethane, chloroform, methanol, a mixture of hexane and ethyl acetate, a mixture of hexane and dichloromethane, a mixture of hexane, ethyl acetate and dichloromethane, a mixture of chloroform and methanol, a mixture of acetic acid and acetonitrile, and the like. In a preferred embodiment, the purification is performed by preparative thin-layer silica gel chromatography, and the developing solvent is a mixture of hexane, ethyl acetate and dichloromethane.

According to some aspects of the present invention, there is provided a method for producing a compound represented by formula (V), comprising the steps of producing a compound represented by formula (III) by any of the production methods described above, removing the protecting group of the alcoholic hydroxyl group at the 4-position of the compound represented by formula (III) to obtain a compound represented by formula (IV), and removing the protecting group of the phenolic hydroxyl group of the compound represented by formula (IV) to obtain a compound represented by formula (V).

(wherein X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group).

(Wherein, _Y1 is hydrogen or OH)
The details of X ₁ , R ₁ to R ₈ , and A in formula (III) are as explained above for the compound represented by formula (III). 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.

According to the above-mentioned production method, a dimer of gallate-type epicatechin or gallate-type epigallocatechin can be efficiently produced using a dimer of gallate-type protected epicatechin or gallate-type protected epigallocatechin produced by self-condensation.

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

In the deprotection step of the compound represented by general formula (III) and the deprotection step of the compound represented by general formula (IV), a known method can be used as the deprotection method.

For example, when an acetyl group is present as the protecting group A of the alcoholic hydroxyl group, the acetyl group can be removed by adding sodium methoxide or the like. As the solvent, for example, methanol can be used. For the removal of the ethoxyethyl group, see Synthesis 2016, 48, 1525-1532.

For example, when a benzyl group is present as one of the protecting groups R ₁ to R ₈ of the phenolic hydroxyl group, the benzyl group can be eliminated by 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.

In some embodiments, the compounds represented by general formula (IV) and the compounds represented by general formula (V) are purified by silica gel column chromatography or preparative thin-layer silica gel chromatography. Examples of the developing solvent and the eluting solvent include, but are not limited to, 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, and a mixed solvent of chloroform and methanol. 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.

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

By using the self-condensation of the gallate-type epigallocatechin protected monomer of the present disclosure, the gallate-type epigallocatechin dimer, which is a compound represented by formula (V-2), can be efficiently produced.

Gallate-type epigatechin dimers are known to have inhibitory activity against excessive cytokine production and antiviral activity.

This gallated epigatechin dimer, like other proanthocyanidins such as non-gallated epigatechin dimer and gallated epigatechin dimer, is expected to exhibit various physiological effects, including antioxidant effects, and is useful in the fields of food, medicine, cosmetics, etc.

According to some aspects of the present invention, the process includes the steps of producing a compound represented by general formula (III) by the above-mentioned production method, reacting the compound represented by general formula (III) with a compound represented by general formula (VII) to obtain a compound represented by general formula (VIII), and

(wherein X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group).

(wherein X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and m is an integer of 2 to 5.)
and removing the protecting group for the phenolic hydroxyl group from the compound represented by general formula (VIII).

(Wherein, _Y2 is hydrogen or OH, and m is 2 to 5.)
Details of _X1 and _R1 to _R8 in formulae (VII) and (VIII) are as explained above for _X1 and _R1 to _R8 of the compound represented by general formula (III). When _X1 in formula (III) is hydrogen, _X1 in formulae (VII) and (VIII) is hydrogen and _Y1 in formula (IX) is hydrogen, and when _X1 in formula (III) is _OR8 , _X1 in formulae (VII) and (VIII) is _OR8 and _Y1 in formula (IX) is OH.

The compound represented by the general formula (VII) is a compound that does not have a protecting group at the 4-position of the flavan-3-ol of the gallate-type epicatechin or gallate-type epigallocatechin, as compared with the compound represented by the general formula (II), and acts as a nucleophile. X ₁ and R ₁ to R ₈ in the compound represented by the general formula (II) are the same as X ₁ and R ₁ to R ₈ in the compound represented by the general formula (VII).

The step of reacting the compound represented by formula (III) with the compound represented by 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.

The solvent used in the step of reacting the compound represented by general formula (III) with the compound represented by 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.

The reaction time for the step of reacting the compound represented by general formula (III) with the compound represented by general formula (VII) is not particularly limited, and can be adjusted appropriately depending on the type of manufacturing raw material and the type of target product. For example, the reaction time can be 5 to 24 hours, but is not limited to this.

The reaction temperature in the step of reacting the compound represented by general formula (III) with the compound represented by general formula (VII) is not particularly limited, and can be adjusted appropriately depending on the type of raw material and the type of the target product. For example, it is preferably room temperature or lower (0°C or higher and 23°C or lower), but is not limited thereto.

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

For example, when benzyl groups are present as the protecting groups R ₁ to R ₈ of the phenolic hydroxyl group, the benzyl groups 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.

The compound represented by formula (III) is a dimer of a protected epicatechin or a protected epigallocatechin of a gallate type produced by self-condensation of a monomer of a protected epicatechin or a protected epigallocatechin of a gallate type represented by general formula (II). This compound is advantageous in that it can be used to efficiently produce a trimer or more of a gallate type epicatechin or a gallate type epigallocatechin multimer.

The medium molecular weight gallate epicatechin or epigallocatechin polymer represented by formula (XI) obtained by the above manufacturing method is expected to exhibit antioxidant, antitumor, antiviral, and anti-inflammatory activities, as well as non-gallate epigatechin and epigallocatechin polymers, and is useful in the fields of food, medicine, cosmetics, etc.

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

(Wherein, m is 2 to 5.)
The compound represented by formula (IX-2) is a compound represented by formula (IX) in which the monomer unit is a gallate-type epigallocatechin, but is a late-type epigallocatechin polymer.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these.

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

Example 2 Synthesis of medium molecular weight gallate epicatechin polymer Compound (3) obtained by self-condensation is reacted with a protected gallate epicatechin (7) using a Lewis acid reaction catalyst Zn(OTf) ₂ to form a trimer- to pentamer condensation product (8). By deprotecting this compound, trimer- to pentamer compounds (9) of gallate epicatechin are produced.

Example 3: Synthesis of gallate-type epigallocatechin dimer When epigallocatechin gallate derivative (12), prepared in three steps from epigallocatechin gallate (11), was treated with zinc triflate, the epigallocatechin gallate derivative (12) was self-condensed (Suda, M. et al., Synthesis 2014, 46, 3351-3355) to produce the resulting dimer (13) in 48% yield. The hydroxyl group of the ethylene glycol group at the 4-position of compound (13) was methylated and then reductively removed using triethylsilane in the presence of Lewis acid to give compound (14) in 50% yield. All 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).

Scheme 3. Synthesis of gallate-type epigallocatechin dimer

Claims (8)

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 .
(In formula (II), X ₁ is hydrogen or OR ₈ , R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group .)
(In formula (III), X ₁ , R ₁ to R ₈ , and OA are the same as defined in formula (II)). The method of claim 1, in which the yield of the compound represented by general formula (III) is 70% or more. 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).
(In formula (VI), X ₁₁ is hydrogen or OR ₁₈ , and R ₁₁ to R ₁₈ each independently represent a protecting group for a phenolic hydroxyl group.) A compound represented by general formula (III):
(In formula (III), _X1 is hydrogen or _OR8 , _R1 to _R8 each independently represent a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group .) 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.
(In formula (III), _X1 is hydrogen or _OR8 , _R1 to _R8 each independently represent a protecting group for a phenolic hydroxyl group, and OA represents an ethoxyethyl group or an ethylene glycol group .) 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).
(wherein X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group).
(In formula (V), Y ₁ is hydrogen or OH.) 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);
(In formula (VII), X ₁ is hydrogen or OR ₈ , and R ₁ to R ₈ each independently represent a protecting group for a phenolic hydroxyl group.)
(In formula (VIII), _X1 is hydrogen or _OR8 , _R1 to _R8 each independently represent a protecting group for a phenolic hydroxyl group, and m is an integer of 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).
(In formula (IX), _Y2 is hydrogen or OH, and m is 1 to 4. ) A compound represented by formula (IX-2).
(In formula (IX-2), m is 2 to 4. )