JP2008013530A - Method for producing xanthone compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a xanthone compound having a semaphorin inhibitory activity and to obtain its intermediate. <P>SOLUTION: The method for producing a xanthone compound comprises a process for subjecting a compound represented by formula (1) [R<SP>1</SP>is a hydrogen atom or a group represented by formula (2) (R<SP>4</SP>is a substituted or nonsubstituted 1-6C alkyl group or the like); R<SP>2</SP>and R<SP>3</SP>are each the same or different and a substituted or nonsubstituted 1-6C alkoxy group or the like] to two molecule condensation to give a compound represented by formula (4). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a method for producing a xanthone compound, and an intermediate in the production of a xanthone compound.

Semaphorin is an endogenous protein that has been identified as a factor that retreats the nerve growth cone and suppresses axon elongation, so far about 20 molecular species are known, but the best studied There is a subfamily gene group called class 3 type. Proteins encoded by these genes are known to have strong neurite outgrowth inhibitory activity and growth cone retraction activity in vitro. Among them, semaphorin 3A (Sema3A) (see Non-Patent Documents 1 and 2) is the best studied, and this protein induces growth cone retraction of cultured neurons in a short time at a low concentration of 10 pM. To do.
As a substance that inhibits the function of semaphorin, it can be obtained from the culture of Penicillium sp. SPF-3059 strain (National Institute of Advanced Industrial Science and Technology, Patent Biodeposition Center accession number: FERM BP-7663) A series of xanthone compounds (see Patent Document 1 or 2) and derivatives obtained by chemically modifying the xanthone compounds (see Patent Document 3) are known, and the compounds have a nerve regeneration promoting action in vivo. Furthermore, the xanthone compound suppresses cell death (apoptosis) during ischemia, for example, retinal neuronal cell death or neuronal cell death in the brain, and exhibits an excellent effect as an effective therapeutic agent or prophylactic agent for ischemic injury. Has been reported (see Patent Document 4).
Under such circumstances, although the activities of the above-described xanthone compounds and derivatives thereof are of great interest, there has been no report on their total synthesis.
WO 02/09756 pamphlet, International Publication No. 03/062243 Pamphlet International Publication No. 03/062440 Pamphlet International Publication No. 2005/053678 Pamphlet Cell, 75, p217 (1993) Cell, 75, p1389 (1993)

The subject of this invention is providing the manufacturing method of the xanthone compound which has semaphorin inhibitory activity, and its intermediate body.

As a result of intensive studies, the present inventors have found a chemical production method of a xanthone compound having semaphorin inhibitory activity for the first time, and have completed the present invention.

That is, the present invention
[1] Formula (1):

［式中、Ｒ¹は、水素原子、式（２）：

[Wherein R ¹ is a hydrogen atom, formula (2):

（式中、Ｒ⁴は、置換もしくは無置換のＣ₁−Ｃ₆アルキル基、置換もしくは無置換のＣ₂−Ｃ₆アルケニル基、置換もしくは無置換のＣ₂−Ｃ₆アルキニル基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルキル基又は置換もしくは無置換のアリール基を表す。）
で表される基、又は式（３）：

Wherein R ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted It represents a C ₃ -C ₇ cycloalkyl group or a substituted or unsubstituted aryl group substituted.)
Or a group represented by formula (3):

（式中、Ｒ⁵は、水素原子又はＣ₁−Ｃ₆アルキル基を表し、
Ｒ⁶は、水素原子、置換もしくは無置換のＣ₁−Ｃ₆アルキル基、置換もしくは無置換のＣ₂−Ｃ₆アルケニル基、置換もしくは無置換のＣ₂−Ｃ₆アルキニル基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基又は置換もしくは無置換の４〜７員の飽和ヘテロ環基を表すか、
あるいはＲ⁵及びＲ⁶は結合して、隣接する窒素原子と共に、置換もしくは無置換の４〜７員の飽和含窒素へテロ環を形成してもよい。）
で表される基を表し、
Ｒ²及びＲ³は、各々同一又は異なって、水素原子、置換もしくは無置換のＣ₁−Ｃ₆アルコキシ基、置換もしくは無置換のＣ₂−Ｃ₆アルケニルオキシ基、置換もしくは無置換のＣ₂−Ｃ₆アルキニルオキシ基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルコキシ基、置換もしくは無置換のＣ₂−Ｃ₇アルカノイルオキシ基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルカノイルオキシ基、置換もしくは無置換のアロイルオキシ基、置換もしくは無置換のアリールオキシ基、置換もしくは無置換のヘテロアロイルオキシ基又は置換もしくは無置換のヘテロアリールオキシ基を表す。］
で表される化合物を、二分子縮合させ、式（４）：

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ² and R ³ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkoxy group, a substituted or unsubstituted C ₂ -C ₆ alkenyloxy group, a substituted or unsubstituted C ₂ -C ₆ alkynyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkoxy group, a substituted or unsubstituted C ₂ -C ₇ alkanoyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkanoyl group, A substituted or unsubstituted aroyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaroyloxy group, or a substituted or unsubstituted heteroaryloxy group is represented. ]
A compound represented by the formula (4):

［式中、Ｒ¹、Ｒ²及びＲ³は、前記と同義を表す。］
で表される化合物を得る工程を含む、キサントン化合物の製造方法；

[Wherein, R ¹ , R ² and R ³ represent the same meaning as described above. ]
A process for producing a xanthone compound, comprising a step of obtaining a compound represented by:

[2] The method for producing a xanthone compound according to [1], wherein bimolecular condensation is performed in the presence of an antioxidant;

[3] The method for producing a xanthone compound according to [2], wherein the antioxidant is a phenolic antioxidant;

[4] The method for producing a xanthone compound according to [3], wherein the phenol-based antioxidant is 2,6-di-tert-butyl-4-methylphenol;

[5] Furthermore, the formula (4):

［式中、Ｒ¹、Ｒ²及びＲ³は、前記〔１〕と同義を表す。］
で表される化合物を脱保護し、式（５）：

[Wherein R ¹ , R ² and R ³ represent the same meaning as in the above [1]. ]
The compound represented by formula (5):

［式中、Ｒ⁷は、水素原子、カルボキシル基、式（２）：

[Wherein R ⁷ represents a hydrogen atom, a carboxyl group, formula (2):

（式中、Ｒ⁴は、置換もしくは無置換のＣ₁−Ｃ₆アルキル基、置換もしくは無置換のＣ₂−Ｃ₆アルケニル基、置換もしくは無置換のＣ₂−Ｃ₆アルキニル基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルキル基又は置換もしくは無置換のアリール基を表す。）
で表される基、又は式（３）：

Wherein R ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted It represents a C ₃ -C ₇ cycloalkyl group or a substituted or unsubstituted aryl group substituted.)
Or a group represented by formula (3):

（式中、Ｒ⁵は、水素原子又はＣ₁−Ｃ₆アルキル基を表し、
Ｒ⁶は、水素原子、置換もしくは無置換のＣ₁−Ｃ₆アルキル基、置換もしくは無置換のＣ₂−Ｃ₆アルケニル基、置換もしくは無置換のＣ₂−Ｃ₆アルキニル基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基又は置換もしくは無置換の４〜７員の飽和ヘテロ環基を表すか、
あるいはＲ⁵及びＲ⁶は結合して、隣接する窒素原子と共に、置換もしくは無置換の４〜７員の飽和含窒素へテロ環を形成してもよい。）
で表される基を表し、
Ｒ⁸及びＲ⁹は、各々同一又は異なって、水素原子、水酸基、置換もしくは無置換のＣ₁−Ｃ₆アルコキシ基、置換もしくは無置換のＣ₂−Ｃ₆アルケニルオキシ基、置換もしくは無置換のＣ₂−Ｃ₆アルキニルオキシ基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルコキシ基、置換もしくは無置換のＣ₂−Ｃ₇アルカノイルオキシ基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルカノイルオキシ基、置換もしくは無置換のアロイルオキシ基、置換もしくは無置換のアリールオキシ基、置換もしくは無置換のヘテロアロイルオキシ基又は置換もしくは無置換のヘテロアリールオキシ基を表す。
但し、少なくとも、Ｒ⁷がカルボキシル基であるか、又は、Ｒ⁸もしくはＲ⁹の少なくとも一方が水酸基である。］
で表される化合物を得る工程を含む、〔１〕〜〔４〕のいずれかに記載のキサントン化合物の製造方法；

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted C ₁ -C ₆ alkoxy group, a substituted or unsubstituted C ₂ -C ₆ alkenyloxy group, a substituted or unsubstituted group. C ₂ -C ₆ alkynyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkoxy group, a substituted or unsubstituted C ₂ -C ₇ alkanoyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkanoyloxy A group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaroyloxy group, or a substituted or unsubstituted heteroaryloxy group;
However, at least R ⁷ is a carboxyl group, or at least one of R ⁸ or R ⁹ is a hydroxyl group. ]
A method for producing a xanthone compound according to any one of [1] to [4], comprising a step of obtaining a compound represented by:

[6] Formula (4A):

［式中、Ｒ^1Aは、水素原子、式（２Ａ）：

[Wherein R ^1A represents a hydrogen atom, formula (2A):

（式中、Ｒ^4Aは、無置換のＣ₁−Ｃ₆アルキル基を表す。）
で表される基、又は式（３）：

(In the formula, R ^4A represents an unsubstituted C ₁ -C ₆ alkyl group.)
Or a group represented by formula (3):

（式中、Ｒ⁵は、水素原子又はＣ₁−Ｃ₆アルキル基を表し、
Ｒ⁶は、水素原子、置換もしくは無置換のＣ₁−Ｃ₆アルキル基、置換もしくは無置換のＣ₂−Ｃ₆アルケニル基、置換もしくは無置換のＣ₂−Ｃ₆アルキニル基、置換もしくは無置換のＣ₃−Ｃ₇シクロアルキル基、置換もしくは無置換のアリール基、置換もしくは無置換のヘテロアリール基又は置換もしくは無置換の４〜７員の飽和ヘテロ環基を表すか、
あるいはＲ⁵及びＲ⁶は結合して、隣接する窒素原子と共に、置換もしくは無置換の４〜７員の飽和含窒素へテロ環を形成してもよい。）
で表される基を表し、
Ｒ^2A及びＲ^3Aは、各々同一又は異なって、水素原子又はメトキシ基を表す。］
で表される化合物を、塩化アルミニウムの存在下で脱保護し、式（５Ａ）：

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ^2A and R ^3A are the same or different and each represents a hydrogen atom or a methoxy group. ]
Is deprotected in the presence of aluminum chloride to give a compound of formula (5A):

［式中、Ｒ^7Aは、水素原子、カルボキシル基、又は式（３）：

[Wherein R ^7A represents a hydrogen atom, a carboxyl group, or formula (3):

（式中、Ｒ⁵及びＲ⁶は、前記と同義を表す。）
で表される基を表し、
Ｒ^8A及びＲ^9Aは、各々同一又は異なって、水素原子、水酸基を表す。］
で表される化合物を得る工程を含む、〔５〕に記載のキサントン化合物の製造方法；

(In the formula, R ⁵ and R ⁶ are as defined above.)
Represents a group represented by
R ^8A and R ^9A are the same or different and each represents a hydrogen atom or a hydroxyl group. ]
A method for producing a xanthone compound according to [5], comprising a step of obtaining a compound represented by:

[7] Formula (1):

［式中、Ｒ¹、Ｒ²及びＲ³は、前記〔１〕と同義を表す。］
で表される化合物を二分子縮合させる工程、及び必要に応じ脱保護する工程を含む、式（５）：

[Wherein R ¹ , R ² and R ³ represent the same meaning as in the above [1]. ]
Including a step of bimolecular condensation of the compound represented by formula (5) and a step of deprotecting as necessary:

［式中、Ｒ⁷、Ｒ⁸及びＲ⁹は、前記〔４〕と同義を表す。］
で表されるキサントン化合物の製造方法；

[Wherein R ⁷ , R ⁸ and R ⁹ have the same meanings as the above [4]. ]
A method for producing a xanthone compound represented by:

[8] Formula (1):

［式中、Ｒ¹、Ｒ²及びＲ³は、前記〔１〕と同義を表す。］
で表される化合物；

[Wherein, R ¹ , R ² and R ³ have the same meanings as the above [1]. ]
A compound represented by:

[9] Formula (1B):

［式中、Ｒ^1Bは、式（２Ｂ）：

[Wherein, R ^1B represents the formula (2B):

（式中、Ｒ^4Bは、置換もしくは無置換のＣ₁−Ｃ₆アルキル基を表す。）
で表される基を表し、
Ｒ^2B及びＲ^3Bは、各々同一又は異なって、置換もしくは無置換のＣ₁−Ｃ₆アルコキシ基を表す。］
で表される、〔８〕に記載の化合物；

(In the formula, R ^4B represents a substituted or unsubstituted C ₁ -C ₆ alkyl group.)
Represents a group represented by
R ^2B and R ^3B are the same or different and each represents a substituted or unsubstituted C ₁ -C ₆ alkoxy group. ]
The compound according to [8], represented by:

[10] The compound represented by the formula (1) is represented by the formula (1B):

［式中、Ｒ^1B、Ｒ^2B及びＲ^3Bは、前記〔９〕と同義を表す。］
で表される化合物である、〔１〕〜〔７〕のいずれかに記載の製造方法
に関するものである。

[Wherein, R ^1B , R ^2B and R ^3B have the same ^meanings as the above [9]. ]
It is related with the manufacturing method in any one of [1]-[7] which is a compound represented by these.

According to the present invention, a xanthone compound having semaphorin inhibitory activity can be chemically produced. The xanthone compound produced according to the present invention is a nerve regeneration promoter in the periphery or the center, as a prophylactic or therapeutic agent for a neuropathic disease or neurodegenerative disease containing such a nerve regeneration promoter, or accompanied by an ischemic disorder. It is useful as a preventive or therapeutic agent for neurological diseases.

  Hereinafter, a method for producing a xanthone compound represented by the formula (4) by condensing two molecules of the compound represented by the formula (1) will be described in detail.

［式中、Ｒ¹、Ｒ²及びＲ³は、前記と同義を表す。］
反応は、溶媒の存在下または非存在下、必要に応じて加温及び／又は加圧して行なう。反応に用いる溶媒としては、ベンゼン、トルエン、ｏ−キシレン、ｍ−キシレン、ｐ−キシレン、キシレン混合物、１，２，４−トリメチルベンゼン、メシチレン（１，３，５−トリメチルベンゼン）、クメン（イソプロピルベンゼン）などの芳香族炭化水素を挙げることができ、好ましくはベンゼン又はトルエンが挙げられる。使用する溶媒の量は、好ましくは原料化合物１ミリモル当たり１ないし１００ミリリットルである。反応温度は室温ないし２５０℃であり、必要に応じシールドチューブ又はオートクレーブを用いることにより、加圧下２５０℃以下の高温下で反応を実施することもできる。反応時間は原料化合物、溶媒及び反応温度により異なるが、概ね１時間ないし数日間である。
反応を行うに当たっては、酸化による副反応又は原料及び／もしくは生成物の分解を抑える為に、反応系内に抗酸化剤を共存させることもできる。抗酸化剤としては、例えば２，６−ジ−ｔ−ブチル−４−メチルフェノール（ＢＨＴ）、２，６−ジ−ｔ−ブチルフェノール、ブチルヒドロキシアニソール（ＢＨＡ）、トコフェロール、６−ヒドロキシ−２，５，７，８−テトラクロロクロマン−２−カルボン酸及びその光学活性体などのフェノール系の抗酸化剤や、ヒドロキノン、ピロカテコール（ｏ−ヒドロキノン）、ｔ−ブチルヒドロキノン（ＴＢＨＱ）などのヒドロキノン系化合物などを挙げることができ、好ましくはフェノール系の抗酸化剤が挙げられ、最も好ましくは２，６−ジ−ｔ−ブチル−４−メチルフェノールが挙げられる。使用する抗酸化剤の量は、原料化合物に対し０．１ないし１０当量、好ましくは１ないし１０当量である。
上述の方法により合成される式（４）で表されるキサントン化合物を、反応液から単離・精製するには、反応生成物の単離・精製において通常使用される手段を用いることができる。すなわち、反応混合物から目的物を単離・精製する場合は、反応混合物からの通常の単離・精製法、例えば溶媒抽出、再結晶、イオン交換樹脂、吸着クロマトグラフィー、分配クロマトグラフィー、ゲル濾過クロマトグラフィー、高速液体クロマトグラフィー（ＨＰＬＣ）、薄層クロマトグラフィー、等を用いることができ、これらの単離・精製法は単独又は組み合わせて行うことができる。

[Wherein, R ¹ , R ² and R ³ represent the same meaning as described above. ]
The reaction is carried out in the presence or absence of a solvent with heating and / or pressurization as necessary. Solvents used in the reaction include benzene, toluene, o-xylene, m-xylene, p-xylene, xylene mixture, 1,2,4-trimethylbenzene, mesitylene (1,3,5-trimethylbenzene), cumene (isopropyl Aromatic hydrocarbons such as benzene), and preferably benzene or toluene. The amount of solvent used is preferably 1 to 100 milliliters per millimole of starting compound. The reaction temperature is from room temperature to 250 ° C. The reaction can be carried out at a high temperature of 250 ° C. or lower under pressure by using a shield tube or an autoclave as necessary. The reaction time varies depending on the raw material compound, the solvent and the reaction temperature, but is generally 1 hour to several days.
In carrying out the reaction, an antioxidant may be allowed to coexist in the reaction system in order to suppress side reactions due to oxidation or decomposition of raw materials and / or products. Examples of the antioxidant include 2,6-di-t-butyl-4-methylphenol (BHT), 2,6-di-t-butylphenol, butylhydroxyanisole (BHA), tocopherol, 6-hydroxy-2, Phenolic antioxidants such as 5,7,8-tetrachlorochroman-2-carboxylic acid and optically active substances thereof, and hydroquinones such as hydroquinone, pyrocatechol (o-hydroquinone) and t-butylhydroquinone (TBHQ) A compound etc. can be mentioned, Preferably a phenolic antioxidant is mentioned, Most preferably, 2, 6-di-t-butyl-4-methylphenol is mentioned. The amount of the antioxidant used is 0.1 to 10 equivalents, preferably 1 to 10 equivalents, relative to the raw material compound.
In order to isolate and purify the xanthone compound represented by the formula (4) synthesized by the above method from the reaction solution, means usually used in the isolation and purification of the reaction product can be used. That is, when isolating and purifying the target product from the reaction mixture, the usual isolation and purification methods from the reaction mixture, such as solvent extraction, recrystallization, ion exchange resin, adsorption chromatography, partition chromatography, gel filtration chromatography, etc. Chromatography, high performance liquid chromatography (HPLC), thin layer chromatography, and the like can be used, and these isolation and purification methods can be performed alone or in combination.

  The xanthone compound represented by the formula (4) obtained by such a method can be led to the xanthone compound represented by the formula (5) by performing appropriate deprotection.

［式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁷、Ｒ⁸及びＲ⁹は、前記と同義を表す。］
すなわち、式（４）におけるＲ¹が式（２）で表される基である場合には、加水分解反応等によりこの基をカルボキシル基へと変換できる。また、式（４）におけるＲ²及び／又はＲ³がアルコキシ基である場合には脱アルキル化反応等により、もしくはアルカノルオキシ基である場合には加水分解反応等により、この基を水酸基へと変換できる。このような脱保護の方法については、例えば「Protective Groups in Organic Synthesis, Second edition」（Theodora W. Greene and Peter G.M. Wuts 編；John Wiley & Sons, Inc., 1991 )等の記載を参照することができる。
例えば、かかる脱保護反応を塩化アルミニウムを試薬として用いて行う場合、反応は、溶媒の存在下または非存在下、必要に応じて加温して行なう。使用する塩化アルミニウムの量は、原料化合物に対し、２ないし５０倍モルである。反応に用いる溶媒としては、好ましくはベンゼン、トルエン、ｏ−キシレン、ｍ−キシレン、ｐ−キシレン、キシレン混合物、１，２，４−トリメチルベンゼン、メシチレン（１，３，５−トリメチルベンゼン）、クメン（イソプロピルベンゼン）などの芳香族炭化水素を挙げることができ、より好ましくはトルエンが挙げられる。使用する溶媒の量は、好ましくは原料化合物１ミリモル当たり１ないし１００ミリリットルである。反応温度は室温ないし溶媒の沸点で反応を実施することもできる。反応時間は原料化合物、溶媒及び反応温度により異なるが、概ね１時間ないし数日間である。

[Wherein, R ¹ , R ² , R ³ , R ⁷ , R ⁸ and R ⁹ represent the same meaning as described above. ]
That is, when R ¹ in formula (4) is a group represented by formula (2), this group can be converted into a carboxyl group by a hydrolysis reaction or the like. Further, when R ² and / or R ³ in the formula (4) is an alkoxy group, this group is converted to a hydroxyl group by a dealkylation reaction or the like, or when it is an alkanoloxy group, by a hydrolysis reaction or the like. And can be converted. For such a deprotection method, for example, refer to the description of “Protective Groups in Organic Synthesis, Second edition” (edited by Theodora W. Greene and Peter GM Wuts; John Wiley & Sons, Inc., 1991). it can.
For example, when this deprotection reaction is carried out using aluminum chloride as a reagent, the reaction is carried out with heating as necessary in the presence or absence of a solvent. The amount of aluminum chloride used is 2 to 50 times mol of the raw material compound. As the solvent used in the reaction, benzene, toluene, o-xylene, m-xylene, p-xylene, xylene mixture, 1,2,4-trimethylbenzene, mesitylene (1,3,5-trimethylbenzene), cumene Aromatic hydrocarbons such as (isopropylbenzene) can be mentioned, and toluene is more preferred. The amount of solvent used is preferably 1 to 100 milliliters per millimole of starting compound. The reaction can be carried out at room temperature to the boiling point of the solvent. The reaction time varies depending on the raw material compound, the solvent and the reaction temperature, but is generally 1 hour to several days.

Moreover, the xanthone represented by another formula (4) is obtained by performing etherification of the carboxyl group and / or esterification and / or etherification of a hydroxyl group of the xanthone compound represented by the formula (5) thus obtained. It can also lead to compounds. For such esterification and etherification methods as well, see, for example, “Protective Groups in Organic Synthesis, Second Edition” (edited by Theodora W. Greene and Peter GM Wuts; John Wiley & Sons, Inc., 1991). can do.

The compound represented by the formula (1) used as the starting compound for this reaction can be synthesized by the following method.

［上記式中、Ｒ¹、Ｒ²及びＲ³は前記と同義である。］
すなわち、式（６）で表される化合物をアクリロニトリルに溶解し、例えば水酸化ベンジルトリメチルアンモニウム（Triton B (R)）のような塩基の存在下で加熱することにより、式（７）で表される化合物とし、このシアノ基を酸性条件下で加水分解することにより、式（８）で表される化合物を導くことができる。式（８）で表される化合物を、トリフルオロ酢酸中、無水トリフルオロ酢酸を用いて環化させることにより、式（９）で表される化合物を導くことができる。続いて式（９）で表される化合物のカルボニル基を、例えばトルエン中p-トルエンスルホン酸のような酸の存在下、過剰量のエチレングリコール及びオルトギ酸トリメチルを用いて加熱することによりアセタール化して、式（１０）で表される化合物を得ることができる。氷冷以下の低温下でブチルリチウムを用い、式（１０）で表される化合物にハロゲン金属交換反応を行った後に、クロロギ酸メチルを導入し、酸性条件下でアセタールの脱保護を行って、式（１１）で表される化合物を得ることができる。必要に応じ、式（１１）で表される化合物のメトキシカルボニル基を酸性又は塩基性条件下に加水分解してカルボキシル基とし、かかるカルボキシル基をエステル化又はアミド化することにより、式（１２）で表される化合物とすることもできる。
カルボキシル基のエステル化の具体的な方法としては、例えばメタノール、エタノール、イソプロピルアルコールのようなアルコール系溶媒中、過剰量のジアゾメタンまたはトリメチルシリルジアゾメタンを滴下して作用させる方法、例えばメタノール、エタノール、イソプロピルアルコールのようなアルコール中、例えば塩酸、硫酸等の無機酸、または、例えばメタンスルホン酸、パラトルエンスルホン酸、トリフルオロメタンスルホン酸、カンファースルホン酸等の有機酸の存在下で加熱する方法、例えばジメチルホルムアミド（ＤＭＦ）、Ｎ−メチルピペリジノン（ＮＭＰ）のような高極性非プロトン性溶媒中、必要に応じて例えばジメチルアミノピリジン（ＤＭＡＰ）、トリエチルアミン、ジイソプロピルエチルアミン等の塩基の存在下、必要に応じて例えば１−ヒドロキシベンゾトリアゾール（ＨＯＢＴ）、１−ヒドロキシ−７−アザベンゾトリアゾール（ＨＯＡＴ）等の添加剤の共存下に、例えば１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド・塩酸塩（ＥＤＣ、ＥＤＣＩあるいはＷＳＣ・ＨＣｌ）、１，３−ジシクロヘキシルカルボジイミド（ＤＣＣ）等の縮合剤を用いて種々のアルコールと縮合させる方法、例えば、ジクロロメタン、テトラヒドロフラン、アセトニトリル等の溶媒中、必要に応じて例えばジメチルアミノピリジン（ＤＭＡＰ）、トリエチルアミン、ジイソプロピルエチルアミン等の塩基の存在下、ピバロイルクロリド等のアシルクロリド、クロロ炭酸イソプロピル等のクロロ炭酸エステル、メタンスルフォニルクロリド等のスルフォニルクロリド、ジメチルスルファモイルクロリド等のスルファモイルクロリド等を作用させて混合酸無水物を経由して種々のアルコールと縮合させる混合酸無水物法等を例示することができる。

[Wherein, R ¹ , R ² and R ³ are as defined above. ]
That is, the compound represented by the formula (6) is dissolved in acrylonitrile and heated in the presence of a base such as benzyltrimethylammonium hydroxide (Triton B (R)), for example, and represented by the formula (7). The compound represented by the formula (8) can be derived by hydrolyzing the cyano group under acidic conditions. By cyclizing the compound represented by the formula (8) using trifluoroacetic anhydride in trifluoroacetic acid, the compound represented by the formula (9) can be derived. Subsequently, the carbonyl group of the compound represented by formula (9) is acetalized by heating with an excess amount of ethylene glycol and trimethyl orthoformate in the presence of an acid such as p-toluenesulfonic acid in toluene. Thus, a compound represented by the formula (10) can be obtained. After performing a halogen metal exchange reaction on the compound represented by the formula (10) using butyl lithium at a low temperature below ice-cooling, methyl chloroformate is introduced, and acetal is deprotected under acidic conditions. A compound represented by the formula (11) can be obtained. If necessary, the methoxycarbonyl group of the compound represented by the formula (11) is hydrolyzed under acidic or basic conditions to form a carboxyl group, and the carboxyl group is esterified or amidated to give the formula (12) It can also be set as the compound represented by these.
Specific examples of the esterification of the carboxyl group include a method in which an excess amount of diazomethane or trimethylsilyldiazomethane is dropped in an alcohol solvent such as methanol, ethanol, isopropyl alcohol, and the like, for example, methanol, ethanol, isopropyl alcohol. A method of heating in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoromethanesulfonic acid or camphorsulfonic acid, such as dimethylformamide In a highly polar aprotic solvent such as (DMF) or N-methylpiperidinone (NMP), the presence of a base such as dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, etc. Under the coexistence of additives such as 1-hydroxybenzotriazole (HOBT) and 1-hydroxy-7-azabenzotriazole (HOAT) as necessary, for example, 1- (3-dimethylaminopropyl) -3- A method of condensing with various alcohols using a condensing agent such as ethyl carbodiimide / hydrochloride (EDC, EDCI or WSC / HCl), 1,3-dicyclohexylcarbodiimide (DCC), for example, in a solvent such as dichloromethane, tetrahydrofuran, acetonitrile, etc. If necessary, for example, in the presence of a base such as dimethylaminopyridine (DMAP), triethylamine or diisopropylethylamine, an acyl chloride such as pivaloyl chloride, a chlorocarbonate such as isopropyl chlorocarbonate, a methanecarbonate such as methanesulfonyl chloride. Fonirukurorido can be exemplified dimethylsulfamoyl chloride sulfamoyl chloride mixed acid anhydride method engaged various alcohols condensed via a mixed acid anhydride by the action of such as such.

Specific examples of the amidation of the carboxyl group include, for example, dimethylaminopyridine (DMAP) in a highly polar aprotic solvent such as dimethylformamide (DMF) and N-methylpiperidinone (NMP) as necessary. ), Triethylamine, diisopropylethylamine and the like, and in the presence of an additive such as 1-hydroxybenzotriazole (HOBT) and 1-hydroxy-7-azabenzotriazole (HOAT) as necessary, for example, 1 -(3-Dimethylaminopropyl) -3-ethylcarbodiimide / hydrochloride (EDC, EDCI or WSC.HCl), 1,3-dicyclohexylcarbodiimide (DCC) and other amines or their salts condensed using a condensing agent For example, dichloromethane, tetra In the presence of a base such as dimethylaminopyridine (DMAP), triethylamine or diisopropylethylamine in a solvent such as lofuran or acetonitrile, if necessary, pivaloyl chloride, isopropyl chlorocarbonate, methanesulfonyl chloride, dimethylsulfamoyl chloride, etc. Examples of the mixed acid anhydride method include a method of reacting with various amines or salts thereof via a mixed acid anhydride.
A compound represented by the formula (13) can be obtained by allowing iodine to act on the compound represented by the formula (12) in dimethyl sulfoxide (DMSO) under heating conditions. Furthermore, the compound represented by the formula (1) is obtained by heating the compound represented by the formula (13) by adding methyl vinyl ketone, triethylamine and a catalytic amount of palladium acetate in acetonitrile. Can do.

In addition, when R < ² > and R < ³ > in Formula (1) are not a hydrogen atom, the compound represented by the above-mentioned formula (6) can be synthesized by the following method.

［上記式中、Ｒ²とＲ³は前記と同義である。Ｒ¹⁰は、１，３−ジオキサン−２−イル基、１，３−ジオソラン−２−イル基、ジメトキシメチル基、ジベンジルオキシメチル基、１，３−ジチアン−２−イル基、１，３−ジチオラン−２−イル基、ジメチルチオメチル基、ジエチルチオメチル基又はジプロピルチオメチル基を表す。Ｒ¹¹は、ピバロイル基又はアリル基を表す。］
すなわち、バニリンのホルミル基および水酸基を保護した後にメチルエーテルを脱保護して、式（１４）で表される化合物とした後に、生じた水酸基を修飾して、引き続きホルミル基および水酸基上の保護基を脱保護することにより、式（１５）で表される化合物を導くことができる。かかるホルミル基および水酸基の保護／脱保護の方法については、例えば「Protective Groups in Organic Synthesis, Second edition」（Theodora W. Greene and Peter G.M. Wuts 編；John Wiley & Sons, Inc., 1991 )等の記載を参照することができる。
水酸基を修飾する方法としては、例えば、アルキル化、アシル化などが挙げられる。

[Wherein, R ² and R ³ are as defined above. R ¹⁰ is 1,3-dioxan-2-yl group, 1,3-diosolan-2-yl group, dimethoxymethyl group, dibenzyloxymethyl group, 1,3-dithian-2-yl group, 1,3 -Represents a dithiolan-2-yl group, a dimethylthiomethyl group, a diethylthiomethyl group or a dipropylthiomethyl group. R ¹¹ represents a pivaloyl group or an allyl group. ]
That is, after protecting the formyl group and hydroxyl group of vanillin, methyl ether is deprotected to obtain a compound represented by the formula (14), and then the resulting hydroxyl group is modified, followed by the formyl group and the protecting group on the hydroxyl group. By deprotecting, the compound represented by the formula (15) can be derived. Such a formyl group and hydroxyl group protection / deprotection method is described in, for example, “Protective Groups in Organic Synthesis, Second Edition” (edited by Theodora W. Greene and Peter GM Wuts; John Wiley & Sons, Inc., 1991). Can be referred to.
Examples of the method for modifying the hydroxyl group include alkylation and acylation.

As a reaction solvent for alkylation of a hydroxyl group, for example, a highly polar aprotic solvent such as dimethylformamide (DMF) and N-methylpiperidinone (NMP), or dichloromethane, 1,2-dichloroethane, chlorobenzene and dichlorobenzene. Halogen-based solvents such as are preferable, and the base to be used is cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, water Inorganic bases such as sodium oxide and lithium hydroxide, and pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole, sodium methoxide, sodium ethoxide, t-butoxypotassium Include organic bases are.
Alkylating agents applicable to this synthesis method include dimethyl sulfate, for example, alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, such as benzyl bromide, 2-fluorobenzyl bromide. Alkyl halides having substituents such as 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 3-methoxybenzyl bromide, alkenyl halides such as allyl iodide, allyl bromide, and the like. However, it is not limited to these. When the halogen atom in the reagent such as alkyl halide is a bromine atom or a chlorine atom, a phase transfer catalyst such as tetrabutylammonium iodide or benzyltributylammonium iodide, or a metal iodide such as sodium iodide, if necessary. May coexist.

Further, the acylation of such a hydroxyl group is performed by, for example, a highly polar aprotic solvent such as dimethylformamide (DMF) or N-methylpiperidinone (NMP), or dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, etc. In organic solvents such as pyridine, lutidine, collidine, dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, imidazole, sodium methoxide, sodium ethoxide, t-butoxypotassium or the like, or cesium carbonate, potassium carbonate, carbonate Reaction of acylating agents in the presence of inorganic bases such as sodium, lithium carbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide To be synthesized by.
Examples of acylating agents applicable to this synthesis method include acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, such as acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, 2-fluorobenzoyl chloride, 3- Acid chlorides such as fluorobenzoyl, 4-fluorobenzoyl chloride and 4-methoxybenzoyl chloride can be exemplified, but of course not limited thereto.
Next, by reacting the compound represented by the formula (15) with bromine in an acetic acid solvent, only the ortho position of the phenolic hydroxyl group is regioselectively brominated and represented by the formula (16). A compound can be obtained. The hydroxyl group on the compound represented by the formula (16) is alkylated or acylated by the above-mentioned method to obtain the compound represented by the formula (17), and then, using a chloroperbenzoic acid in dichloromethane, Vaeyer-Villiger By oxidizing the resulting formyl ester in methanol using a base such as triethylamine, the target compound represented by the formula (6) can be synthesized.

The compound in which R ³ in formula (1) is a hydrogen atom can be synthesized by using commercially available 3-bromo-4-hydroxybenzaldehyde as the compound represented by formula (16).
A compound in which R ² in formula (1) is a hydrogen atom can be synthesized, for example, by the method of GC Dol et al. (Described in Eur. J. Org. Chem., 1998, pages 359 to 364) 3,5 -It can synthesize | combine by protecting only one of the two hydroxyl groups of dihydroxy bromobenzene, and using as a compound represented by Formula (6). For the protection of such hydroxyl groups, refer to the description of, for example, “Protective Groups in Organic Synthesis, Second Edition” (edited by Theodora W. Greene and Peter GM Wuts; John Wiley & Sons, Inc., 1991). It can carry out by restrict | limiting to 0.5-1.5 equivalent.
Further, a compound in which R ¹ in formula (1) is a hydrogen atom is also led from the compound represented by formula (18) to the compound represented by formula (20) by any one of the following routes. It can synthesize | combine by using it instead of the compound represented by the above-mentioned formula (12).

すなわち式（２０）で表される化合物は、杉原らの方法（Chem. Pharm. Bull. 誌、1977年、25巻、859〜866頁に記載）に従い、式（１８）で表される化合物をジメチルホルムアミド中水素化ナトリウムでアニオン化し、引き続きβ−プロピオラクトンと反応させて式（１９）で表される化合物とした後、ポリリン酸中で環化させるか、または、森らの方法（Eur. J. Org. Chem.誌、2001年、1963〜1966頁に記載）に従い、式（１８）で表される化合物を、１当量の三フッ化ホウ素・エーテル錯塩の存在下、塩化クロロプロピオニルと反応させて式（２１）で表される化合物とした後、アルコール中で塩基処理して環化させることにより入手することができる。
なお、式（１８）で表される化合物は、これまでに上述した方法を適宜組み合わせることにより、市販のレゾルシノール、レゾルシノールモノアセテート、レゾルシノールモノベンゾエート、ヒドロキノン、３，４−ジヒドロキシベンズアルデヒド、バニリン等から合成することができる。

That is, the compound represented by the formula (20) is obtained from the compound represented by the formula (18) according to the method of Sugihara et al. (Described in Chem. Pharm. Bull., 1977, 25, pages 859 to 866). Anionization with sodium hydride in dimethylformamide followed by reaction with β-propiolactone to give a compound of formula (19), followed by cyclization in polyphosphoric acid or by the method of Mori et al. (Eur J. Org. Chem., 2001, pp. 1963 to 1966), the compound represented by the formula (18) is reacted with chloropropionyl chloride in the presence of 1 equivalent of boron trifluoride-ether complex. After making it react and it is set as the compound represented by Formula (21), it can obtain by base-treating in alcohol and making it cyclize.
The compound represented by the formula (18) is synthesized from commercially available resorcinol, resorcinol monoacetate, resorcinol monobenzoate, hydroquinone, 3,4-dihydroxybenzaldehyde, vanillin and the like by appropriately combining the above-described methods. can do.

The substituents of the compound in the present invention will be described below.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The C ₁ -C ₆ alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, a 2-propyl group (isopropyl group), A butyl group, 2-methylpropyl group, 3-methylpropyl group (isobutyl group), t-butyl group, pentyl group, neopentyl group, hexyl group and the like can be exemplified.
The C ₂ -C ₆ alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a 1-propenyl group, a 2-propenyl group, or a 1-methylvinyl group. 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-ethylvinyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-1-propenyl group, 2-methyl 2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-propylvinyl group, 1-ethyl-2-propenyl group, 1-methyl-3-butenyl group, 1,3-butadienyl group, 1-methyl-1-butenyl group, 1-ethyl-3-methylvinyl group, 1-methyl-1-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-to Xenyl And the like can be given. Preferred examples include a vinyl group (ethenyl group), a cis-1-propenyl group, a trans-1-propenyl group, an allyl group (2-propenyl group), and an isopropenyl group (1-methylvinyl group).
The C ₂ -C ₆ alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group, or a 1-butynyl group. 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 5-hexynyl group, etc. Can be mentioned. Preferably, an ethynyl group, 1-propynyl group, 2-propynyl group, etc. can be mentioned.

A C3-C7 cycloalkyl group means a _{3- to 7} -membered cycloalkyl group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
The aryl group means a monocyclic or bicyclic 6 to 10 membered aromatic hydrocarbon group, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
The heteroaryl group includes 5 to 4 heteroatoms selected from monocyclic or bicyclic 0 to 4 nitrogen atoms, 0 to 1 oxygen atoms and 0 to 1 sulfur atoms. A 10-membered heteroaryl group. Specifically, pyrrolyl group, pyridyl (nitrogen atom may be oxidized) group, pyrimidyl group, thienyl group, furyl group, imidazolyl group, triazolyl group, tetrazolyl group, indolyl group, quinolyl group, prill group, A quinazolinyl group, a benzimidazolyl group, a benzthiazolyl group, etc. can be mentioned.
The 4- to 7-membered saturated heterocycle includes 4 to 7 containing 1 to 4 heteroatoms selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms. Member saturated heterocycle. Specific examples include azetidine, pyrrolidine, piperidine, piperazine, morpholine, oxirane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, ethylene sulfide, tetrahydrothiophene, pentamethylene sulfide or 1,4-thioxan.

The 4- to 7-membered saturated nitrogen-containing heterocycle formed by combining R ⁵ and R ⁶ together with the adjacent nitrogen atom includes 1 to 3 nitrogen atoms, 0 to 4 oxygen atoms, and 0 to 1 Examples thereof include 4 to 7-membered saturated nitrogen-containing heterocycles containing 1 to 4 heteroatoms selected from sulfur atoms. Examples of the saturated nitrogen-containing heterocycle include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide or perhydroazepine.

The C ₁ -C ₆ alkoxy group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, t -A butoxy group, a pentoxy group, a hexyloxy group, etc. can be mentioned.
The C ₂ -C ₆ alkenyloxy group means a straight or branched alkenyloxy group having 2 to 6 carbon atoms, specifically, a vinyloxy group (ethenyloxy group), a cis-1-propenyloxy group, trans A -1-propenyloxy group, an allyloxy group (2-propenyloxy group), an isopropenyloxy group (1-methylvinyloxy group), and the like can be given.
The C ₂ -C ₆ alkenyloxycarbonyl group represents a group in which a carbonyl is bonded to the C ₂ -C ₆ alkenyloxy group.
The C ₂ -C ₆ alkynyloxy group means a linear or branched alkynyloxy group having 2 to 6 carbon atoms, specifically, an ethynyloxy group, a 1-propynyloxy group, a 2-propynyloxy group, and the like. Can be mentioned.
The C ₂ -C ₆ alkynyloxycarbonyl group represents a group in which a carbonyl is bonded to the C ₂ -C ₆ alkynyloxy group.
The C ₃ -C ₇ cycloalkoxy group includes cycloalkoxy groups 3-7 membered, specifically cyclopropyl group, cyclobutyl group, cyclopentyloxy group, cyclohexyloxy group, a Puchiruokishi group cyclohexane Can be mentioned.
The C ₂ -C ₇ alkanoyl group means a linear or branched alkanoyl group having 2 to 7 carbon atoms, and specifically includes an acetyl group, a propionyl group, a butyryl group (butanoyl group), an isobutyryl group (2 -Methylpropanoyl group), valeryl group (pentanoyl group), isovaleryl group (3-methylbutanoyl group), pivaloyl group or hexanoyl group.
The C ₂ -C ₇ alkanoyloxy group means a linear or branched alkanoyloxy group having 2 to 7 carbon atoms, specifically, an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, A valeryloxy group, an isovaleryloxy group, a pivaloyloxy group, a hexanoyloxy group, etc. can be mentioned.
Examples of the C ₃ -C ₇ cycloalkanoyloxy group include a _{3- to} 7-membered cycloalkanoyloxy group, specifically a cyclopropylcarbonyloxy group, a cyclobutylcarbonyloxy group, a cyclopentylcarbonyloxy group, and a cyclohexylcarbonyloxy group. And cycloheptylcarbonyloxy group.
Specific examples of the aroyl group include a benzoyl group, a 1-naphthoyl group, and a 2-naphthoyl group.
Specific examples of the aroyloxy group include a benzoyloxy group, a 1-naphthoyloxy group, and a 2-naphthoyloxy group.
Specific examples of the aryloxy group include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.
The heteroaroyl group represents a group in which a carbonyl group is bonded to a carbon atom on the heteroaryl group, and specifically includes a pyrrolylcarbonyl group (for example, 2-pyrrolylcarbonyl group), pyridylcarbonyl (a nitrogen atom is an oxide). Group (for example, 2-pyridylcarbonyl group, 4-pyridylcarbonyl group, etc.), pyrimidinylcarbonyl group (for example, 4-pyrimidinylcarbonyl group, etc.), thienylcarbonyl group (for example, 2-thienylcarbonyl group). , 3-thienylcarbonyl group, etc.), furylcarbonyl group (eg, 2-furylcarbonyl group, 3-furylcarbonyl group, etc.), imidazolylcarbonyl group (eg, 4-imidazolylcarbonyl group, etc.), quinolylcarbonyl group (2-quinoyl group, etc.). Arylcarbonyl group, etc.), purinylcarbonyl group (2- Linylcarbonyl group etc.), quinazolinylcarbonyl group (6-quinazolinylcarbonyl group etc.), benzimidazolylcarbonyl group (2-benzimidazolylcarbonyl group etc.) or benzthiazolylcarbonyl group (2-benzthiazolyl) Carbonyl group and the like).
The heteroaroyloxy group represents a group in which a carbonyloxy group is bonded to a carbon atom on the heteroaryl group. Specifically, a pyrrolylcarbonyloxy group (for example, 2-pyrrolylcarbonyloxy group), pyridyl Carbonyloxy (nitrogen atom may be oxidized) group (for example, 2-pyridylcarbonyloxy group, 4-pyridylcarbonyloxy group, etc.), pyrimidinylcarbonyloxy group (for example, 4-pyrimidylcarbonyloxy group, etc.) ), Thienylcarbonyloxy group (eg, 2-thienylcarbonyloxy group, 3-thienylcarbonyloxy group, etc.), furylcarbonyloxy group (eg, 2-furylcarbonyloxy group, 3-furylcarbonyloxy group, etc.), imidazolylcarbonyl An oxy group (eg 4-imidazolylcarbonyloxy) Group), quinolylcarbonyloxy group (2-quinolylcarbonyloxy group etc.), purinylcarbonyloxy group (2-prinylcarbonyloxy group etc.), quinazolinylcarbonyloxy group (6-quinazolinylcarbonyloxy group) Group), a benzimidazolylcarbonyloxy group (2-benzimidazolylcarbonyloxy group, etc.) or a benzthiazolylcarbonyloxy group (2-benzthiazolylcarbonyloxy group, etc.).
The heteroaryloxy group represents a group in which an oxygen atom is bonded to a carbon atom on the heteroaryl group, and specifically represents a group in which a carbonyloxy group is bonded to a carbon atom on the heteroaryl group. Specifically, pyrrolyloxy group (for example, 2-pyrrolyloxy group), pyridyloxy (nitrogen atom may be oxidized) group (for example, 2-pyridyloxy group, 4-pyridyloxy group, etc.), pyrimidinyloxy group (For example, 4-pyrimidinyloxy group, etc.), thienyloxy group (for example, 2-thienyloxy group, 3-thienyloxy group, etc.), furyloxy group (for example, 2-furyloxy group, 3-furyloxy group, etc.) Imidazolyloxy group (for example, 4-imidazolyloxy group), quinolyloxy group (2-quinolyloxy group, etc.), purinyloxy group (2- Purinyloxy group, etc.), quinazolinyloxy group (6-quinazolinyloxy group, etc.), benzimidazolyloxy group (2-benzimidazolyloxy group, etc.) or benzthiazolyloxy group (2-benzthiazolyloxy group) Etc.).

Examples of the “alkoxy” in the C ₂ -C ₇ alkoxycarbonyl group include the same as those described above for the alkoxy group.

In the present specification, when a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group and a C ₂ -C ₆ alkynyl group are substituted, it is substituted with 1 or more, preferably 1 to 5 substituents. May be. As the substituent, a halogen atom, a hydroxyl group, a substituted or unsubstituted C ₁ -C ₆ alkoxy group, a substituted or unsubstituted C ₂ -C ₇ alkanoyl group, a substituted or unsubstituted C ₂ -C ₇ alkanoyloxy group , substituted or unsubstituted C ₂ -C ₇ alkoxycarbonyl group, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted And a 4- to 7-membered saturated heterocyclic group, a substituted or unsubstituted amino group, or a substituted or unsubstituted carbamoyl group.
In the present specification, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkenyloxy group, a C ₁ -C ₆ alkynyloxy group, a C ₂ -C ₇ alkanoyl group, a C ₂ -C ₇ alkanoyloxy group, and C _{If 2} -C ₇ alkoxycarbonyl group is substituted, one or more, preferably may be substituted with 1-5 substituents. Examples of the substituent include a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₇ alkanoyl group, a C ₂ -C ₇ alkanoyloxy group, a C ₂ -C ₇ alkoxycarbonyl group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₂ -C ₇ alkanoylamino groups, C ₁ -C ₆ alkoxycarbonylamino group, a carbamoyl group, C ₁ -C ₆ alkylcarbamoyl group, di C ₁ -C ₆ alkylcarbamoyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or the like is a saturated heterocyclic group or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7 membered Can be mentioned.
In the present specification, the two alkyl groups in the di-C ₁ -C ₆ alkylamino group and the di-C ₁ -C ₆ alkylcarbamoyl group are synonymous with the above “alkyl group” and may be the same or different.

In this specification, the substituent in the case where the amino group is substituted, substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₁ -C ₆ alkenyl group, a substituted or unsubstituted C ₁ -C ₆ alkynyl group, a substituted or unsubstituted C ₁ -C ₆ alkanoyl group, a substituted or unsubstituted aroyl group, a substituted or unsubstituted heteroaroyl group, a substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl group Substituted or unsubstituted C ₁ -C ₆ alkenyloxycarbonyl group, substituted or unsubstituted C ₁ -C ₆ alkynyloxycarbonyl group, substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkyl group, substituted or An unsubstituted heteroaryl group or a substituted or unsubstituted 4- to 7-membered saturated heterocyclic group, and the like. Ku may be substituted by two substituents.

Substituents of the amino group, substituted C ₁ -C ₆ alkyl group, a substituted C ₁ -C ₆ alkenyl group, a substituted C ₁ -C ₆ alkynyl group, a substituted C ₁ -C ₆ alkanoyl group, a substituted C ₁ -C ₆ alkoxycarbonyl group, may represent a substituted C ₁ -C ₆ alkenyloxycarbonyl group or a substituted C ₁ -C ₆ alkynyloxy group, one or more, preferably may be substituted with 1-5 substituents. As the substituent, a halogen atom, a hydroxyl group, a carboxyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₂ -C ₇ alkanoyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₃ - C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted 4-7-membered saturated heterocyclic group, a substituted or unsubstituted aroyl group or a substituted or unsubstituted Examples include substituted heteroaroyl groups.

In the present specification, when the carbamoyl group is substituted, the substituent is 1 or 2 identical or different C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkenyl groups, C ₁ -C ₆ alkynyl groups, Examples thereof include a substituted or unsubstituted aryl group or a substituted or unsubstituted cycloalkyl group, which may be substituted with the same or different 1 or 2 substituents.

In the present specification, when a cycloalkyl group, a cycloalkoxy group or a cycloalkanoyloxy group is substituted, it may be substituted with one or more, preferably 1 to 5 substituents. As the substituent, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino groups include C ₂ -C ₇ alkoxycarbonyl group.
In the present specification, when a 4- to 7-membered saturated heterocyclic group or a 4- to 7-membered saturated nitrogen-containing heterocycle is substituted, any carbon atom or nitrogen atom is maintained as long as a stable chemical structure is maintained. Above, it may be substituted with one or more, preferably 1-5 substituents. As the substituent, a halogen atom, a hydroxyl group, a carboxyl group, an amino group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino groups include C ₂ -C ₇ alkoxycarbonyl group.
In the present specification, when the aryl group, aryloxy group, aroyl group, aroyloxy group, heteroaryl group, heteroaryloxy group, heteroaroyl group or heteroaroyloxy group is substituted, one or more, preferably 1 to 5 It may be substituted with one substituent. The examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, a carboxyl group, an amino group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₂ -C ₇ alkanoyl group, C ₂ - C ₇ alkanoyloxy group, C ₂ -C ₇ alkoxycarbonyl group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylcarbamoyl group or a di-C ₁ -C ₆ alkyl And a carbamoyl group.

R ¹ is preferably a hydrogen atom or a group represented by the formula (2).
R ⁴ is preferably a C ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group.
R ² and R ³ are preferably a hydrogen atom, a substituted or unsubstituted C ₁ -C ₃ alkoxy group or a C ₁ -C ₃ alkanoyloxy group, more preferably a methoxy group, a substituted or unsubstituted benzyl group. Acetyl group or substituted or unsubstituted benzoyl group.

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples. However, the technical scope of the present invention is not limited to these examples.
The structures of the compounds of Examples and Reference Examples were determined by ¹ H NMR spectrum or fast electron impact mass spectrum. ^For measurement of ¹ H NMR spectrum, JEOL AL 400 or AL 300 was used, and tetramethylsilane was used as an internal standard. JEOL SX102A and JEOL GC mate were used for measurement of the high-speed electron impact mass spectrum.
The compounds of Examples and Reference Examples were purified using thin layer chromatography or the like. Silica gel 60 F ₂₅₄ (Art. 5715) manufactured by Merck & Co. was used for thin layer chromatography, and a UV lamp, a sodium phosphomolybdate-ethanol solution, and an anisaldehyde-acetic acid-sulfuric acid-ethanol solution were used for detection.

(Reference Example 1)
3-Bromo-4-hydroxy-5-methoxybenzaldehyde

バニリン 20.4 g (134.6 mmol)を酢酸102.0 mlに溶解した後、氷冷下、臭素 11.7 ml (228.8 mmol)を滴加し、室温で6時間かきまぜた。沈殿物をろ過した後、ろ物を蒸留水で洗浄した。ろ物を減圧下乾燥し、標記化合物 29.3 g (126.8 mmol)を白色粉末状物質として得た(収率94.2 %)。
Ｒ_f値 0.47 (１，２−ジクロロエタン：酢酸エチル = 10 : 1)
¹H NMR (300 MHz, CDCl₃): δ 4.00 (3H, s), 6.495 (1H, s), 7.36 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 2.0 Hz), 9.79 (1H, s)

（参考例２）
３−ブロモ−４，５−ジメトキシベンズアルデヒド

After dissolving 20.4 g (134.6 mmol) of vanillin in 102.0 ml of acetic acid, 11.7 ml (228.8 mmol) of bromine was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. After filtering the precipitate, the filtrate was washed with distilled water. The residue was dried under reduced pressure to obtain 29.3 g (126.8 mmol) of the title compound as a white powder (yield 94.2%).
R _f value 0.47 (1,2-dichloroethane: ethyl acetate = 10: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 4.00 (3H, s), 6.495 (1H, s), 7.36 (1H, d, J = 2.0 Hz), 7.64 (1H, d, J = 2.0 Hz), 9.79 (1H, s)

(Reference Example 2)
3-Bromo-4,5-dimethoxybenzaldehyde

参考例１で得られた化合物 59.74 g (258.5 mmol)をアセトン(600 mL)に溶解し、炭酸カリウム60.75 g (439.5 mmol)及びジメチル硫酸34.2 mL (361.9 m mol)を加え50℃で9.5時間かきまぜた。不溶の炭酸カリウムをろ過にて除去した後、ろ液を減圧下濃縮した。残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 560 g、へキサン : 酢酸エチル= 5 : 1）で精製し、標記化合物 59.34 g (242.1 mmol)を白色粉末状物質として得た(収率93.6 %)。
Ｒ_f値 0.54 (ヘキサン：酢酸エチル = 2 : 1)
¹H NMR (300 MHz, CDCl₃): δ 3.94 (3H, s), 3.96 (3H, s), 7.39 (1H, d, J = 2.0 Hz), 7.66 (1H, d, J = 2.0 Hz), 9.85 (1H, s)

（参考例３）
３−ブロモ−４，５−ジメトキシフェノール

59.74 g (258.5 mmol) of the compound obtained in Reference Example 1 was dissolved in acetone (600 mL), 60.75 g (439.5 mmol) of potassium carbonate and 34.2 mL (361.9 mmol) of dimethyl sulfate were added, and the mixture was stirred at 50 ° C. for 9.5 hours. It was. Insoluble potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (BW-820MH 560 g, hexane: ethyl acetate = 5: 1, manufactured by Fuji Silysia Chemical Ltd.) to give 59.34 g (242.1 mmol) of the title compound as a white powder. Obtained (yield 93.6%).
R _f value 0.54 (hexane: ethyl acetate = 2: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 3.94 (3H, s), 3.96 (3H, s), 7.39 (1H, d, J = 2.0 Hz), 7.66 (1H, d, J = 2.0 Hz), 9.85 (1H, s)

(Reference Example 3)
3-Bromo-4,5-dimethoxyphenol

参考例２で得られた化合物 4.87 g (19.87 mmol)をジクロロメタン(97.8 mL)に溶解し、メタクロロ安息香酸(最高含量77%) 6.68 g (29.8 mmol)を加えた後、39℃で11時間かきまぜた。反応終了後、反応溶液に飽和炭酸水素ナトリウム(25.0 mL)及び飽和チオ硫酸ナトリウム水溶液(25.0 mL)を加え、クロロホルム(500mL)を加えて分液した後、新たにクロロホルム(300mL)を加えて抽出した。合わせた有機層を減圧下濃縮し、橙色固体7.58gを得た。得られた反応残渣を0.1Mトリエチルアミン含有メタノール溶液(151.6 mL)に溶解した後、室温で2時間放置した。
反応終了後、反応溶媒を減圧下留去し、残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 127 g、へキサン : 酢酸エチル= 3 : 1）で精製し、標記化合物 3.71 g (15.91 mmol)を白色固体として得た(収率80.1 %)。
Ｒ_f値 0.34 (へキサン：酢酸エチル = 2 : 1)
¹H NMR (300 MHz, CDCl₃) : δ 3.79 (3H, s), 3.84 (3H, s), 4.80 (1H, s), 6.41 (1H, d, J = 3.0 Hz), 6.60 (1H, d, J = 3.0 Hz)
高速電子衝撃質量スペクトル（FAB-MS）: 233[M+H]⁺

（参考例４）
３−（３−ブロモ−４，５−ジメトキシフェノキシ）プロピオニトリル

Dissolve 4.87 g (19.87 mmol) of the compound obtained in Reference Example 2 in dichloromethane (97.8 mL), add metachlorobenzoic acid (maximum content 77%) 6.68 g (29.8 mmol), and stir at 39 ° C. for 11 hours. It was. After completion of the reaction, saturated sodium bicarbonate (25.0 mL) and saturated aqueous sodium thiosulfate solution (25.0 mL) were added to the reaction solution, chloroform (500 mL) was added to separate the solution, and chloroform (300 mL) was newly added for extraction. did. The combined organic layers were concentrated under reduced pressure to obtain 7.58 g of an orange solid. The obtained reaction residue was dissolved in 0.1 M triethylamine-containing methanol solution (151.6 mL), and then allowed to stand at room temperature for 2 hours.
After completion of the reaction, the reaction solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia Chemical Ltd. BW-820MH 127 g, hexane: ethyl acetate = 3: 1) Compound 3.71 g (15.91 mmol) was obtained as a white solid (yield 80.1%).
R _f value 0.34 (hexane: ethyl acetate = 2: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 3.79 (3H, s), 3.84 (3H, s), 4.80 (1H, s), 6.41 (1H, d, J = 3.0 Hz), 6.60 (1H, d , J = 3.0 Hz)
Fast electron impact mass spectrum (FAB-MS): 233 [M + H] ⁺

(Reference Example 4)
3- (3-Bromo-4,5-dimethoxyphenoxy) propionitrile

参考例３で得られた化合物 10.87 g (46.64 mmol)をアクリロニトリル(108.7 mL)に溶解した後、トリトンB (40%メタノール溶液) 2.11 mL (4.66 mmol)を加え、75℃で48時間加熱した。減圧下反応溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 490 g、トルエン : アセトニトリル= 20 : 1）で精製し、標記化合物 8.44 g (29.62 mmol)を白色固体として得た(収率63.2 %)。
Ｒ_f値 0.36 (トルエン：アセトニトリル = 15 : 1)
¹H NMR (400 MHz, CDCl₃): δ 2.81 (2H, t, J = 4.0 Hz), 3.80 (3H, s), 3.85 (3H, s), 4.14 (2H, t, J = 4.0 Hz), 6.49 (1H, d, J = 2.0 Hz), 6.61 (1H, d, J = 2.0 Hz)
高速電子衝撃質量スペクトル（FAB-MS）: 286[M+H]⁺

（参考例５）
３−（３−ブロモ−４，５−ジメトキシフェノキシ）プロピオン酸

After 10.87 g (46.64 mmol) of the compound obtained in Reference Example 3 was dissolved in acrylonitrile (108.7 mL), 2.11 mL (4.66 mmol) of Triton B (40% methanol solution) was added and heated at 75 ° C. for 48 hours. The reaction solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (BW-820MH 490 g, toluene: acetonitrile = 20: 1, manufactured by Fuji Silysia Chemical Ltd.) and the title compound 8.44 g (29.62 mmol) ) Was obtained as a white solid (63.2% yield).
R _f value 0.36 (toluene: acetonitrile = 15: 1)
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.81 (2H, t, J = 4.0 Hz), 3.80 (3H, s), 3.85 (3H, s), 4.14 (2H, t, J = 4.0 Hz), 6.49 (1H, d, J = 2.0 Hz), 6.61 (1H, d, J = 2.0 Hz)
Fast electron impact mass spectrum (FAB-MS): 286 [M + H] ⁺

(Reference Example 5)
3- (3-Bromo-4,5-dimethoxyphenoxy) propionic acid

参考例４で得られた化合物 4.25 g (14.85 mmol)に9M 塩酸水溶液 (42.5 mL)を加え80℃で10時間かき混ぜた。反応終了後、氷冷下にて水40 mLを加え、クロロホルム320 mLで水層を2回抽出した。減圧下濃縮し、残留物20.98 gを得た。残留物をシリカゲル36.0 gに吸着させ、シリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 500 g、ヘキサン : 酢酸エチル= 2 : 1）で精製し標記化合物 4.02 g (13.22 mmol)を白色固体として得た(収率89.1 %)。
Ｒ_f値 0.50 (酢酸エチル)
¹H NMR (300 MHz, CDCl₃): δ 2.77 (2H, t, J = 6.0Hz), 3.72 (3H, s), 3.76 (3H, s), 4.12 (2H, t, J = 6.0Hz), 6.39 (1H, d, J = 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz)
高速電子衝撃質量スペクトル（FAB-MS）: 305[M+H]⁺

（参考例６）
５−ブロモ−６，７−ジメトキシクロマン−４−オン

To 4.25 g (14.85 mmol) of the compound obtained in Reference Example 4, 9M hydrochloric acid aqueous solution (42.5 mL) was added and stirred at 80 ° C. for 10 hours. After completion of the reaction, 40 mL of water was added under ice cooling, and the aqueous layer was extracted twice with 320 mL of chloroform. Concentration under reduced pressure gave 20.98 g of residue. The residue was adsorbed on 36.0 g of silica gel and purified by silica gel column chromatography (BW-820MH 500 g, hexane: ethyl acetate = 2: 1) manufactured by Fuji Silysia Chemical Ltd. to obtain 4.02 g (13.22 mmol) of the title compound. Obtained as a white solid (yield 89.1%).
R _f value 0.50 (ethyl acetate)
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.77 (2H, t, J = 6.0Hz), 3.72 (3H, s), 3.76 (3H, s), 4.12 (2H, t, J = 6.0Hz), 6.39 (1H, d, J = 2.5 Hz), 6.59 (1H, d, J = 2.5 Hz)
Fast electron impact mass spectrum (FAB-MS): 305 [M + H] ⁺

(Reference Example 6)
5-Bromo-6,7-dimethoxychroman-4-one

参考例５で得られた化合物 7.82 g (25.62 mmol)をトリフルオロ酢酸39.1 mLに溶解したのち、無水トリフルオロ酢酸5.34 mL (38.39 mmol)を加え、室温にて2時間放置した。減圧下反応溶媒を留去し、淡黄色固体10.65gを得た。残留物をシリカゲル20.0 gに吸着させ、シリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 225g、ヘキサン : 酢酸エチル= 3 : 1）で精製し、標記化合物 7.08 g (24.65 mmol)を白色固体として得た(収率96.2 %)。
Ｒ_f値 0.33 (ヘキサン：酢酸エチル = 2 : 1)
¹H NMR (300 MHz, CDCl₃): δ 2.72 (2H, t, J = 6.0 Hz), 3.72 (3H, s), 3.84 (3H, s), 4.42 (2H, t, J = 6.0 Hz), 6.39 (1H, s)
高速電子衝撃質量スペクトル（FAB-MS）: 287[M+H]⁺

（参考例７）
５−ブロモ−２，３−ジヒドロ−６，７−ジメトキシスピロ（４Ｈ−１−ベンゾピラン−４，２’−［１，３］ジオキソラン

After 7.82 g (25.62 mmol) of the compound obtained in Reference Example 5 was dissolved in 39.1 mL of trifluoroacetic acid, 5.34 mL (38.39 mmol) of trifluoroacetic anhydride was added and left at room temperature for 2 hours. The reaction solvent was distilled off under reduced pressure to obtain 10.65 g of a pale yellow solid. The residue was adsorbed onto 20.0 g of silica gel and purified by silica gel column chromatography (BW-820MH 225 g, hexane: ethyl acetate = 3: 1, manufactured by Fuji Silysia Chemical Ltd.) to give 7.08 g (24.65 mmol) of the title compound. Obtained as a white solid (96.2% yield).
R _f value 0.33 (hexane: ethyl acetate = 2: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.72 (2H, t, J = 6.0 Hz), 3.72 (3H, s), 3.84 (3H, s), 4.42 (2H, t, J = 6.0 Hz), 6.39 (1H, s)
Fast electron impact mass spectrum (FAB-MS): 287 [M + H] ⁺

(Reference Example 7)
5-Bromo-2,3-dihydro-6,7-dimethoxyspiro (4H-1-benzopyran-4,2 ′-[1,3] dioxolane

参考例６で得られた化合物 7.08 g (24.65 mmol)をトルエン141.6 mL に溶解し、エチレングリコール6.80 mL (123.29 mmol)、オルトギ酸トリメチル10.78 mL (98.53 mmol)及びトシル酸一水和物937.6mg (4.93 mmol)を加え、80℃で11時間加熱した。反応終了後、飽和炭酸水素ナトリウム水溶液40.0 mLを加えて分液操作を行った後、酢酸エチル150.0 mLで抽出した。合わせた有機層を減圧下濃縮し、残留物8.96gを得た。残留物をシリカゲル15.0 gに吸着させ、シリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 162 g、ヘキサン : 酢酸エチル= 2 : 1）で精製し、標記化合物 6.77 g (20.51 mmol)を白色固体として得た(収率83.2 %)。
Ｒ_f値 0.45 (ヘキサン：酢酸エチル = 2 : 1)
¹H NMR (400 MHz, CDCl₃): δ 2.11-2.14 (2H, m), 3.75 (3H, s), 3.80 (3H, s), 4.09-4.13 (2H, m), 4.17-4.21 (2H, m), 4.35-4.39 (2H, m), 6.35 (1H, s)

（参考例８）
６，７−ジメトキシ−４−オキソクロマン−５−カルボン酸 メチルエステル

7.08 g (24.65 mmol) of the compound obtained in Reference Example 6 was dissolved in 141.6 mL of toluene, 6.80 mL (123.29 mmol) of ethylene glycol, 10.78 mL (98.53 mmol) of trimethyl orthoformate, and 937.6 mg of tosylic acid monohydrate ( 4.93 mmol) was added and heated at 80 ° C. for 11 hours. After completion of the reaction, 40.0 mL of saturated aqueous sodium hydrogen carbonate solution was added to carry out a liquid separation operation, followed by extraction with 150.0 mL of ethyl acetate. The combined organic layers were concentrated under reduced pressure to obtain 8.96 g of residue. The residue was adsorbed on 15.0 g of silica gel and purified by silica gel column chromatography (BW-820MH 162 g, hexane: ethyl acetate = 2: 1, manufactured by Fuji Silysia Chemical Ltd.) and the title compound 6.77 g (20.51 mmol) Was obtained as a white solid (yield 83.2%).
R _f value 0.45 (hexane: ethyl acetate = 2: 1)
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.11-2.14 (2H, m), 3.75 (3H, s), 3.80 (3H, s), 4.09-4.13 (2H, m), 4.17-4.21 (2H, m), 4.35-4.39 (2H, m), 6.35 (1H, s)

(Reference Example 8)
6,7-Dimethoxy-4-oxochroman-5-carboxylic acid methyl ester

アルゴン雰囲気下、参考例７で得られた化合物 9.81 g (29.72 mmol)をテトラヒドロフラン 400.0 mLに溶解し、-78℃下にてn-ブチルリチウム(2.55M ヘキサン溶液) 30.0 mL (74.31 mmol)を滴加し、同温にて30分間かきまぜた。-78℃下にてクロロギ酸メチル34.1 mL (445.65 mmol)を加えた後、1時間かきまぜた。酢酸4.25 mL (74.31 mmol)を加え、室温に昇温した。減圧下濃縮し、飽和炭酸水素ナトリウム水溶液50.0 mLを加え、酢酸エチル200.0 mLで抽出した。有機層を減圧下濃縮し、黄色シロップ状物質15.6 gを得た。シリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 330g、ヘキサン : 酢酸エチル = 5 : 2）で精製し、黄色シロップ状物質4.71 gを得た。得られた黄色シロップ状物質に対して5%塩化水素-メタノール溶液95 mLを加え、室温で1時間放置した。反応溶媒を減圧下濃縮し、残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 100 g、ヘキサン : 酢酸エチル= 3 : 2）で精製し、標記化合物 3.36 g (12.63 mmol)を白色固体として得た(収率44.0 %)。
Ｒ_f値 0.31 (ヘキサン：酢酸エチル = 2 : 1)
¹H NMR (300 MHz, CDCl₃): δ 2.71 (2H, t, J = 7.0 Hz), 3.78 (3H, s), 3.88 (3H, s), 3.97 (3H, s), 4.49 (2H, t, J = 7.0 Hz), 6.47 (1H, s)

（参考例９）
３−ヨード−６，７−ジメトキシ−４−オキソ−４Ｈ−クロメン−５−カルボン酸 メチルエステル

Under argon atmosphere, 9.81 g (29.72 mmol) of the compound obtained in Reference Example 7 was dissolved in 400.0 mL of tetrahydrofuran, and 30.0 mL (74.31 mmol) of n-butyllithium (2.55M hexane solution) was added dropwise at −78 ° C. And stirred at the same temperature for 30 minutes. After adding 34.1 mL (445.65 mmol) of methyl chloroformate at −78 ° C., the mixture was stirred for 1 hour. Acetic acid 4.25 mL (74.31 mmol) was added, and the temperature was raised to room temperature. The mixture was concentrated under reduced pressure, 50.0 mL of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with 200.0 mL of ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 15.6 g of a yellow syrup-like substance. Purification by silica gel column chromatography (BW-820MH 330 g, hexane: ethyl acetate = 5: 2 manufactured by Fuji Silysia Chemical Ltd.) gave 4.71 g of a yellow syrup-like substance. To the obtained yellow syrup-like substance, 95 mL of a 5% hydrogen chloride-methanol solution was added and left at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (BW-820MH 100 g, hexane: ethyl acetate = 3: 2 manufactured by Fuji Silysia Chemical Ltd.) to give 3.36 g (12.63 mmol) of the title compound. ) Was obtained as a white solid (yield 44.0%).
R _f value 0.31 (hexane: ethyl acetate = 2: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.71 (2H, t, J = 7.0 Hz), 3.78 (3H, s), 3.88 (3H, s), 3.97 (3H, s), 4.49 (2H, t , J = 7.0 Hz), 6.47 (1H, s)

(Reference Example 9)
3-Iodo-6,7-dimethoxy-4-oxo-4H-chromene-5-carboxylic acid methyl ester

参考例８で得られた化合物 2.33 g (8.77 mmol)をジメチルスルフォキシド11.6 mLに溶解し、ヨウ素2.67 g (10.53 mmol)を加え窒素雰囲気下、110℃で5時間加熱した。飽和チオ硫酸ナトリウム水溶液8.5 mLを加えた後、減圧下濃縮し、残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 170 g、クロロホルム : 酢酸エチル= 20 : 1）で精製し、標記化合物 2.21 g (5.66 mmol)を白色固体として得た(収率64.6 %)。
Ｒ_f値 0.26 (クロロホルム：酢酸エチル = 20 : 1)
¹H NMR (300 MHz, CDCl₃): δ 3.86 (3H, s), 3.97 (3H, s), 4.1 (3H, s), 6.89 (1H, s), 8.18 (1H, s)
高速電子衝撃質量スペクトル（FAB-MS）: 391[M+H]⁺

The compound 2.33 g (8.77 mmol) obtained in Reference Example 8 was dissolved in 11.6 mL of dimethyl sulfoxide, 2.67 g (10.53 mmol) of iodine was added, and the mixture was heated at 110 ° C. for 5 hours in a nitrogen atmosphere. Add 8.5 mL of saturated aqueous sodium thiosulfate solution, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (BW-820MH 170 g, chloroform: ethyl acetate = 20: 1, manufactured by Fuji Silysia Chemical Ltd.) Thus, 2.21 g (5.66 mmol) of the title compound was obtained as a white solid (yield 64.6%).
R _f value 0.26 (chloroform: ethyl acetate = 20: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 3.86 (3H, s), 3.97 (3H, s), 4.1 (3H, s), 6.89 (1H, s), 8.18 (1H, s)
Fast electron impact mass spectrum (FAB-MS): 391 [M + H] ⁺

6,7-Dimethoxy-4-oxo-3-((E) -3-oxo-1-butenyl) -4H-chromene-5-carboxylic acid methyl ester

参考例９で得られた化合物 806.1 mg (2.066 mmol)をアセトニトリル28 mLに溶解し、窒素雰囲に気下、酢酸パラジウム92.8 mg (0.4133 mmol)、メチルビニルケトン 252.6 μL (3.100 mmol)及びトリエチルアミン 432.1 μL (3.100 mmol)を加え50℃で7.5時間加熱した。反応終了後、不溶物をセライトろ過により除去した。ろ液を減圧下濃縮し、残留物1.533 gを得た。残留物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 60g、クロロホルム : メチルエチルケトン = 6 : 1）で精製し淡黄色固体608.3 mgを得た。さらにシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 15 g、ベンゼン : 酢酸エチル = 1 : 1）で精製し、標記化合物 599.9 mg (1.805 mmol)を淡黄色粉末状物質として得た(収率87.3 %)。
Ｒ_f値 0.31 (クロロホルム：メチルエチルケトン = 6 : 1), Ｒ_f値 0.35 (ベンゼン：酢酸エチル = 1 : 1)
¹H NMR (300 MHz, CDCl₃): δ 2.27 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 6.87 (1H, s), 7.21 (1H, d, J = 15.0 Hz), 7.35 (1H, d, J = 15.0 Hz), 8.0 (1H, s)
高速電子衝撃質量スペクトル（FAB-MS）: 333[M+H]⁺

806.1 mg (2.066 mmol) of the compound obtained in Reference Example 9 was dissolved in 28 mL of acetonitrile, and 92.8 mg (0.4133 mmol) of palladium acetate, 252.6 μL of methyl vinyl ketone (3.100 mmol) and triethylamine 432.1 in an atmosphere of nitrogen. μL (3.100 mmol) was added and heated at 50 ° C. for 7.5 hours. After completion of the reaction, insoluble matters were removed by celite filtration. The filtrate was concentrated under reduced pressure to obtain 1.533 g of residue. The residue was purified by silica gel column chromatography (BW-820MH 60 g, chloroform: methyl ethyl ketone = 6: 1, manufactured by Fuji Silysia Chemical Ltd.) to obtain 608.3 mg of a pale yellow solid. Further purification by silica gel column chromatography (BW-820MH 15 g, benzene: ethyl acetate = 1: 1 by Fuji Silysia Chemical Ltd.) gave 599.9 mg (1.805 mmol) of the title compound as a pale yellow powder. (Yield 87.3%).
R _f value 0.31 (chloroform: methyl ethyl ketone = 6: 1), R _f value 0.35 (benzene: ethyl acetate = 1: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.27 (3H, s), 3.81 (3H, s), 3.93 (3H, s), 3.99 (3H, s), 6.87 (1H, s), 7.21 (1H , d, J = 15.0 Hz), 7.35 (1H, d, J = 15.0 Hz), 8.0 (1H, s)
Fast electron impact mass spectrum (FAB-MS): 333 [M + H] ⁺

5,7-Diacetyl-6- (6,7-dimethoxy-5-methoxycarbonyl-4-oxo-4H-chromen-3-yl) -2,3-dimethoxy-9-oxo-9H-xanthene-1-carvone Acid methyl ester

シールドチューブ(容積5 mL)に、実施例１で得られた化合物 20.8 mg (0.0625 mmol)、２，６−ジ−ｔ−ブチル−４−メチルフェノール 55.8 mg (0.2532 mmol)及びトルエン 630 μLを加え、200℃で24時間加熱した。反応溶媒を減圧下濃縮し、残留物88.3 mgを得た。残留物をシリカゲル0.2 gに吸着させ、シリカゲルカラムクロマトグラフィー（関東化学（株）社製Silica Gel 60N (球状、中性、40-50 μm) 2.1 g、1,2-ジクロロエタン : メチルエチルケトン = 7 : 1）で精製し目的物である標記化合物を含む淡黄色固体4.4 mgを得た。また未反応の原料化合物を含む淡黄色固体11.3 mgを得た。
標記化合物を含む淡黄色固体をシリカゲルカラムクロマトグラフィー（関東化学（株）社製Silica Gel 60N (球状、中性、40-50 μm) 225 mg、ベンゼン : 酢酸エチル = 1 : 1）で精製し、標記化合物 3.8 mg (0.0056 mmol)を淡黄色粉末状物質として得た(収率 18.4 %, 回収原料分を差し引いた収率33.3 %)。さらに未反応の原料化合物を含む淡黄色固体をシリカゲルカラムクロマトグラフィー（関東化学（株）社製Silica Gel 60N (球状、中性、40-50 μm) 225 mg、ベンゼン : 酢酸エチル = 1 : 1）で精製し標記化合物 9.4 mg (0.0282 mmol)を淡黄色粉末状物質として得た。
Ｒ_f値 0.28 (１，２−ジクロロエタン：メチルエチルケトン = 7 : 1), Ｒ_f値 0.61 (ベンゼン：酢酸エチル = 1 : 1)
¹H NMR (300 MHz, CDCl₃): δ 2.42 (3H, s), 2.58 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 3.99 (3H, s), 4.01 (3H, s), 4.07 (3H, s), 6.92 (1H, s), 6.94 (1H, s), 7.82 (1H, s), 8.60 (1H, s)
高速電子衝撃質量スペクトル（FAB-MS）: 661[M+H]⁺ ,
高分解能高速電子衝撃スペクトル（HRFAB-MS）: 実測値 661.1546，計算値 661.1557

To the shield tube (volume 5 mL), add 20.8 mg (0.0625 mmol) of the compound obtained in Example 1, 55.8 mg (0.2532 mmol) of 2,6-di-t-butyl-4-methylphenol and 630 μL of toluene. And heated at 200 ° C. for 24 hours. The reaction solvent was concentrated under reduced pressure to obtain 88.3 mg of residue. The residue was adsorbed onto 0.2 g of silica gel, and silica gel column chromatography (Silica Gel 60N (spherical, neutral, 40-50 μm) manufactured by Kanto Chemical Co., Ltd.) 2.1 g, 1,2-dichloroethane: methyl ethyl ketone = 7: 1 To obtain 4.4 mg of a pale yellow solid containing the title compound as a target product. In addition, 11.3 mg of a pale yellow solid containing an unreacted raw material compound was obtained.
The pale yellow solid containing the title compound was purified by silica gel column chromatography (Silica Gel 60N (spherical, neutral, 40-50 μm) 225 mg, benzene: ethyl acetate = 1: 1) manufactured by Kanto Chemical Co., Inc. The title compound (3.8 mg, 0.0056 mmol) was obtained as a pale yellow powder (yield 18.4%, yield 33.3% minus the recovered raw material). Silica gel column chromatography (silica gel 60N (spherical, neutral, 40-50 μm) 225 mg, benzene: ethyl acetate = 1: 1) containing a light yellow solid containing unreacted starting compounds To obtain 9.4 mg (0.0282 mmol) of the title compound as a pale yellow powder.
R _f value 0.28 (1,2-dichloroethane: methyl ethyl ketone = 7: 1), R _f value 0.61 (benzene: ethyl acetate = 1: 1)
¹ H NMR (300 MHz, CDCl ₃ ): δ 2.42 (3H, s), 2.58 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 3.99 (3H , s), 4.01 (3H, s), 4.07 (3H, s), 6.92 (1H, s), 6.94 (1H, s), 7.82 (1H, s), 8.60 (1H, s)
Fast electron impact mass spectrum (FAB-MS): 661 [M + H] ⁺ ,
High-resolution high-speed electron impact spectrum (HRFAB-MS): Measured value 661.1546, Calculated value 661.1557

Binaxanthone

アルゴン雰囲気下、実施例２で得られた化合物 1.4mg (0.00219 mmol)に塩化アルミニウム 3.3mg ( 0.0254 mmol)及びトルエン 98 μLを加え、100℃で8時間かき混ぜた。反応終了後、氷冷下にてトルエン100 μLを加えた後、上清を抜き取った。新たにトルエン 100 μLを加え不溶物を洗浄した後、上清を抜きとり、不溶物を減圧下乾燥した。不溶物をシリカゲルカラムクロマトグラフィー（富士シリシア化学（株）社製BW-820MH 210 mg、 n-ブタノール : 水 : ギ酸 = 8 : 2 : 1）で精製し茶色固体1.3 mgを得た。茶色固体1.3mgをメタノール : ジメチルスフォキシド = 10 : 1 19.5μLに溶解し、トルエン195 μL×5を加えてゆき、生成した沈殿物をスパーテルでこすり、上清を抜き取った。さらにトルエン325 μL×3で沈殿物を洗浄した後、上清を抜き取り、沈殿物を減圧下乾燥し、標記化合物 0.7 mg (0.00121 mmol)を茶色粉末状物質として得た(収率58.3 %)。
Ｒ_f値 0.45 (ｎ−ブタノール : 水 : ギ酸= 8 : 2 : 1)
¹H NMR (300 MHz, DMSO-d₆): δ 2.52 (3H, s), 2.54 (3H, s), 6.92 (1H, s), 6.94 (1H, s), 8.16 (1H, s), 8.52 (1H, s)
高速電子衝撃質量スペクトル（FAB-MS）: 577[M+H]⁺,
高分解能高速電子衝撃スペクトル（HRFAB-MS）: 実測値 577.0615，計算値 577.0618

Under an argon atmosphere, 3.3 mg (0.0254 mmol) of aluminum chloride and 98 μL of toluene were added to 1.4 mg (0.00219 mmol) of the compound obtained in Example 2, and the mixture was stirred at 100 ° C. for 8 hours. After completion of the reaction, 100 μL of toluene was added under ice cooling, and then the supernatant was extracted. After 100 μL of toluene was newly added to wash insoluble matters, the supernatant was taken out and the insoluble matters were dried under reduced pressure. The insoluble material was purified by silica gel column chromatography (BW-820MH 210 mg, n-butanol: water: formic acid = 8: 2: 1 manufactured by Fuji Silysia Chemical Ltd.) to obtain 1.3 mg of a brown solid. 1.3 mg of a brown solid was dissolved in methanol: dimethyl sulfoxide = 10: 1 19.5 μL, toluene 195 μL × 5 was added, the resulting precipitate was rubbed with a spatula, and the supernatant was extracted. Further, after washing the precipitate with toluene 325 μL × 3, the supernatant was taken out and the precipitate was dried under reduced pressure to obtain 0.7 mg (0.00121 mmol) of the title compound as a brown powdery substance (yield 58.3%).
R _f value 0.45 (n-butanol: water: formic acid = 8: 2: 1)
¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.52 (3H, s), 2.54 (3H, s), 6.92 (1H, s), 6.94 (1H, s), 8.16 (1H, s), 8.52 (1H, s)
Fast electron impact mass spectrum (FAB-MS): 577 [M + H] ⁺ ,
High resolution high-speed electron impact spectrum (HRFAB-MS): Measured value 577.0615, Calculated value 577.0618

The present invention relates to a xanthone compound or a pharmaceutically acceptable salt thereof, which has semaphorin inhibitory activity and can be used as a prophylactic or therapeutic agent for neuropathic diseases, neurodegenerative diseases, or neurological diseases associated with ischemic disorders. It is useful as a method for producing the product and its intermediate.

Claims (6)

Formula (1):

[Wherein R ¹ is a hydrogen atom, formula (2):

Wherein R ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted It represents a C ₃ -C ₇ cycloalkyl group or a substituted or unsubstituted aryl group substituted.)
Or a group represented by formula (3):

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ² and R ³ are the same or different and each represents a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkoxy group, a substituted or unsubstituted C ₂ -C ₆ alkenyloxy group, a substituted or unsubstituted C ₂ -C ₆ alkynyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkoxy group, a substituted or unsubstituted C ₂ -C ₇ alkanoyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkanoyl group, A substituted or unsubstituted aroyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaroyloxy group, or a substituted or unsubstituted heteroaryloxy group is represented. ]
A compound represented by the formula (4):

[Wherein, R ¹ , R ² and R ³ represent the same meaning as described above. ]
The manufacturing method of a xanthone compound including the process of obtaining the compound represented by these.
The method for producing a xanthone compound according to claim 1, wherein bimolecular condensation is performed in the presence of an antioxidant.
The method for producing a xanthone compound according to claim 2, wherein the antioxidant is 2,6-di-tert-butyl-4-methylphenol.
Furthermore, Formula (4):

[Wherein R ¹ , R ² and R ³ represent the same meaning as in claim 1. ]
The compound represented by formula (5):

[Wherein R ⁷ represents a hydrogen atom, a carboxyl group, formula (2):

Wherein R ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted It represents a C ₃ -C ₇ cycloalkyl group or a substituted or unsubstituted aryl group substituted.)
Or a group represented by formula (3):

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted C ₁ -C ₆ alkoxy group, a substituted or unsubstituted C ₂ -C ₆ alkenyloxy group, a substituted or unsubstituted group. C ₂ -C ₆ alkynyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkoxy group, a substituted or unsubstituted C ₂ -C ₇ alkanoyloxy group, a substituted or unsubstituted C ₃ -C ₇ cycloalkanoyloxy A group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted heteroaroyloxy group, or a substituted or unsubstituted heteroaryloxy group;
However, at least R ⁷ is a carboxyl group, or at least one of R ⁸ or R ⁹ is a hydroxyl group. ]
The manufacturing method of the xanthone compound of any one of Claims 1-3 including the process of obtaining the compound represented by these.
Formula (4A):

[Wherein R ^1A represents a hydrogen atom, formula (2A):

(In the formula, R ^4A represents an unsubstituted C ₁ -C ₆ alkyl group.)
Or a group represented by formula (3):

(Wherein R ⁵ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ⁶ is a hydrogen atom, a substituted or unsubstituted C ₁ -C ₆ alkyl group, a substituted or unsubstituted C ₂ -C ₆ alkenyl group, a substituted or unsubstituted C ₂ -C ₆ alkynyl group, substituted or unsubstituted C ₃ -C ₇ cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted 4-7-membered saturated heterocyclic group,
Alternatively, R ⁵ and R ⁶ may combine to form a substituted or unsubstituted 4- to 7-membered saturated nitrogen-containing heterocycle with the adjacent nitrogen atom. )
Represents a group represented by
R ^2A and R ^3A are the same or different and each represents a hydrogen atom or a methoxy group. ]
Is deprotected in the presence of aluminum chloride to give a compound of formula (5A):

[Wherein R ^7A represents a hydrogen atom, a carboxyl group, or formula (3):

(In the formula, R ⁵ and R ⁶ are as defined above.)
Represents a group represented by
R ^8A and R ^9A are the same or different and each represents a hydrogen atom or a hydroxyl group. ]
The manufacturing method of the xanthone compound of Claim 4 including the process of obtaining the compound represented by these.
Formula (1):

[Wherein R ¹ , R ² and R ³ represent the same meaning as in claim 1. ]
A compound represented by