JP2008239513A - New method for producing chafuroside based on efficient flavone construction - Google Patents

New method for producing chafuroside based on efficient flavone construction Download PDF

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JP2008239513A
JP2008239513A JP2007079311A JP2007079311A JP2008239513A JP 2008239513 A JP2008239513 A JP 2008239513A JP 2007079311 A JP2007079311 A JP 2007079311A JP 2007079311 A JP2007079311 A JP 2007079311A JP 2008239513 A JP2008239513 A JP 2008239513A
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hydroxyl group
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halogen atom
chafuroside
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JP2008239513A5 (en
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Toshiyuki Suga
敏幸 菅
Takumi Furuta
巧 古田
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University of Shizuoka
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Abstract

<P>PROBLEM TO BE SOLVED: To solve the most serious technical problem in the production of chafuroside comprising the securement of a large quantity of chafuroside, which is caused by the fact that chafuroside is a substance separated from oolong tea, and the separation of only about 800 μg of the substance necessitates a large quantity of oolong tea and requires extremely difficult purification technique. <P>SOLUTION: A large quantity of chafuroside expressed by the chemical formula shown below can be secured by developing a method for synthesizing chafuroside utilizing the induction to a β-diketone by an acyl group introducing reaction, a flavone ring closing reaction and Mitsunobu reaction. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

この発明は、抗炎症薬の有効成分等として有用な Chafuroside 等のフラボン類の製法に関する。   The present invention relates to a method for producing flavones such as Chafuroside useful as an active ingredient of an anti-inflammatory drug.

アトピー性皮膚炎を始めとした炎症に対して使用されるステロイド類は、対症療法的に使用されるのみであり、かつ極めて重篤な副作用を有することも良く知られている。現在のところステロイド類に代わる新規な薬物は知られておらず、その開発は急務の課題となっている。
一方、フラボンC配糖体が抗アレルギー作用を示すことが知られているが（特許文献1）、これは烏龍茶から単離された物質であり800μｇほど単離するために248Lもの烏龍茶を必要とし、その精製も困難を極める。そのため、現在のところ、その量的確保が最大の技術的問題点となっている。
特開2004−35474 It is well known that steroids used for inflammation including atopic dermatitis are only used for symptomatic therapy and have extremely serious side effects. At present, no new drugs to replace steroids are known, and their development is an urgent issue.
On the other hand, it is known that flavone C glycoside has an anti-allergic action (Patent Document 1), which is a substance isolated from oolong tea and requires 248L of oolong tea to isolate about 800μg. The purification is extremely difficult. Therefore, at present, securing the quantity is the biggest technical problem.
JP2004-35474

本発明者らは、アシル基導入反応によるβ−ジケトンへの誘導、フラボン閉環反応、光延反応を効果的に利用して、Chafuroside を合成する新規な方法を開拓し、Chafuroside の量的確保を可能にした。   The present inventors have pioneered a new method for synthesizing Chafuroside by effectively using induction to β-diketone by acyl group introduction reaction, flavone ring closure reaction, and Mitsunobu reaction, and can secure quantitative quantity of Chafuroside. I made it.

即ち、本発明は、非プロトン性溶媒中で下式（化1）

Figure 2008239513
（式中、R 1 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R2 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物と下式（化2）
Figure 2008239513
（式中、R3 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R4 はベンツトリアゾール基、イミダゾール基、ハロゲン原子、エステル基を表す。）で表される化合物とを塩基存在下で反応させる第1段階、及びプロトン性あるいは非プロトン性溶媒中で下式（化3）
Figure 2008239513
（式中、R5 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 6 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R7 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物を酸の存在下で反応させる第2段階、及び非プロトン性溶媒中で下式（化4）
Figure 2008239513
（式中、R8 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 9 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R10 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物を、アゾジカルボン酸アミド又はアゾジカルボン酸エステル及びトリアルキルホスフィン又はトリアリールホスフィンの存在下又はホスホラン類の存在下で反応させる第3段階を含む下式（化5）
Figure 2008239513
 で表される Chafuroside 等のフラボン類の製法である。 That is, the present invention provides the following formula (Formula 1) in an aprotic solvent:
Figure 2008239513
 (In the formula, R 1 represents a hydroxyl group, a protected hydroxyl group, an ether group or an ester group, and a halogen atom, and R 2 may be the same or different from each other, and may be a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected group. And a compound represented by the following formula (Chemical formula 2):
Figure 2008239513
(Wherein R 3 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 4 represents a benztriazole group, an imidazole group or a halogen atom; Represents the ester group.) In the first step of reacting with the compound represented by the base in the presence of a base, and in the protic or aprotic solvent:
Figure 2008239513
(Wherein R 5 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 6 represents a hydroxyl group, a protected hydroxyl group or an ether group; Or an ester group and a halogen atom, and R 7 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, or a sugar such as glucose). A second step in which the compound represented is reacted in the presence of an acid, and in an aprotic solvent:
Figure 2008239513
(Wherein R 8 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 9 represents a hydroxyl group, a protected hydroxyl group or an ether group; Or an ester group and a halogen atom, and R 10 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, or a sugar such as glucose). The following formula comprising a third step in which the compound represented is reacted in the presence of an azodicarboxylic amide or azodicarboxylic acid ester and a trialkylphosphine or triarylphosphine or in the presence of phosphoranes (Formula 5)
Figure 2008239513
 This is a method for producing flavones such as Chafuroside.

本発明は、新規な抗炎症薬 Chafuroside に関するものであり、アトピー性皮膚炎を始めとしたアレルギー疾患治療分野における学術的な効果は極めて大きい。また、本発明により得られるChafuroside及び合成中間体が新規な治療薬の開発に直接結びついた場合、学術的な意義のみでなく、医療上の貢献度、さらには経済的な波及効果も多大なものとなることが期待される。また本製法を利用することで記憶改善作用が期待されるフラボン類の創製にも発展可能である。   The present invention relates to a novel anti-inflammatory drug, Chafuroside, and has a great academic effect in the field of treatment of allergic diseases including atopic dermatitis. In addition, when the Chafuroside and synthetic intermediate obtained by the present invention are directly linked to the development of a novel therapeutic agent, not only the academic significance but also the medical contribution and further the economic ripple effect It is expected to be Moreover, it can be developed to create flavones expected to improve memory by using this production method.

本発明の製法では下式（化1）

Figure 2008239513

で表される化合物を用いる。
式中、R1 は水素原子又はアルキル基、アシル基、ハロゲン原子、水酸基、保護された水酸基を表す。この保護基として、例えば、ベンジル基（Bn）、アルキル基（メチル基、MOM基等）、TES基、TBDMS基、TBDPS基、TIPS基等のシリル基等のエーテル系の保護基、アセチル基等のエステル基系の保護基が挙げられる。
R2 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、ハロゲン原子、グルコース等の糖類、水酸基、保護された水酸基を表す。この保護基として、例えば、ベンジル基（Bn）、アルキル基（メチル基、MOM基等）、TES基、TBDMS基、TBDPS基、TIPS基等のシリル基等のエーテル系の保護基、アセチル基等のエステル基系の保護基が挙げられる。 In the production method of the present invention, the following formula (Chemical Formula 1)
Figure 2008239513
The compound represented by these is used.
In the formula, R 1 represents a hydrogen atom or an alkyl group, an acyl group, a halogen atom, a hydroxyl group, or a protected hydroxyl group. Examples of this protecting group include benzyl groups (Bn), alkyl groups (methyl groups, MOM groups, etc.), ether-type protecting groups such as silyl groups such as TES groups, TBDMS groups, TBDPS groups, TIPS groups, acetyl groups, etc. And an ester group-based protecting group.
R 2 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a halogen atom, a sugar such as glucose, a hydroxyl group, or a protected hydroxyl group. Examples of this protecting group include benzyl groups (Bn), alkyl groups (methyl groups, MOM groups, etc.), ether-type protecting groups such as silyl groups such as TES groups, TBDMS groups, TBDPS groups, TIPS groups, acetyl groups, etc. And an ester group-based protecting group.

このような一般式（化1）で表される化合物として下記のような化合物が挙げられる。

Figure 2008239513

（式中、水酸基は保護されていてもよい。） Examples of the compound represented by the general formula (Formula 1) include the following compounds.
Figure 2008239513
(In the formula, the hydroxyl group may be protected.)

また本発明の製法では下式（化2）

Figure 2008239513

で表される化合物を用いる。
R3 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R4 はベンツトリアゾール基、イミダゾール基、ハロゲン原子、エステル基を表す。 In the production method of the present invention, the following formula (Chemical Formula 2)
Figure 2008239513
The compound represented by these is used.
R 3 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, or a halogen atom, and R 4 represents a benztriazole group, an imidazole group, a halogen atom, or an ester group. To express.

このような一般式（化2）で表される化合物として下記のような化合物が挙げられる。

Figure 2008239513

（式中、水酸基は保護されていてもよい。） Examples of the compound represented by the general formula (Formula 2) include the following compounds.
Figure 2008239513
(In the formula, the hydroxyl group may be protected.)

また本発明の製法では下式（化3）

Figure 2008239513

で表される化合物を用いる。
R5 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 6 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R7 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。 In the production method of the present invention, the following formula (Chemical Formula 3)
Figure 2008239513
The compound represented by these is used.
R 5 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, R 6 represents a hydroxyl group, a protected hydroxyl group, an ether group or an ester group, Represents a halogen atom, and R 7 may be the same or different, and represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, a saccharide such as glucose.

このような一般式（化3）で表される化合物として下記のような化合物が挙げられる。

Figure 2008239513

（式中、水酸基は保護されていてもよい。） Examples of the compound represented by the general formula (Formula 3) include the following compounds.
Figure 2008239513
(In the formula, the hydroxyl group may be protected.)

また本発明の製法では下式（化4）

Figure 2008239513
で表される化合物を用いる。
R8 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 9 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R10 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。 In the production method of the present invention, the following formula (Chemical Formula 4)
Figure 2008239513
 The compound represented by these is used.
R 8 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, R 9 represents a hydroxyl group, a protected hydroxyl group, an ether group or an ester group, Represents a halogen atom, and R 10 s may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, a saccharide such as glucose.

このような一般式（化4）で表される化合物として下記のような化合物が挙げられる。

Figure 2008239513
（式中、水酸基は保護されていてもよい。） Examples of the compound represented by the general formula (Formula 4) include the following compounds.
Figure 2008239513
 (In the formula, the hydroxyl group may be protected.)

本発明の製法は、非プロトン性溶媒中で上記一般式（化1）で表される化合物と上記一般式（化2）で表される化合物とを塩基の存在下で反応させる第1段階、及びプロトン性あるいは非プロトン性溶媒中で上記一般式（化3）で表される化合物を酸の存在下反応させる第2段階、及び非プロトン性溶媒中で上記一般式（化4）で表される化合物をアゾジカルボン酸アミド又はアゾジカルボン酸エステル及びトリアルキルホスフィン又はトリアリールホスフィンの存在下又はホスホラン類の存在下で反応させる第3段階から成る。   The production method of the present invention is a first step of reacting a compound represented by the above general formula (Formula 1) and a compound represented by the above general formula (Formula 2) in the presence of a base in an aprotic solvent. And a second step in which a compound represented by the above general formula (Chemical Formula 3) is reacted in the presence of an acid in a protic or aprotic solvent, and represented by the above General Formula (Chemical Formula 4) in an aprotic solvent. In the presence of azodicarboxylic acid amide or azodicarboxylic acid ester and trialkylphosphine or triarylphosphine or in the presence of phosphoranes.

第1段階はアシル基導入反応によりβ−ジケトンへと誘導する反応である。
非プロトン性溶媒としては、トルエン、THF等が挙げられる。
非プロトン性溶媒中の一般式（化1）で表される化合物の濃度は好ましくは0．01−1．OMであり、これに一般式（化2）で表される化合物をほぼ化学量論量加えることが好ましい。
塩基としては、LHMDS, KHMDS, NaHMDS, LDA を用いることができる。
溶媒中の塩基の濃度は通常0．001−1，OM、好ましくは0．01−0．1Mである。
反応温度は通常−78−100℃、好ましくは一20−30℃で行われる。
この段階の反応により上記一般式（化3）で表される有用な中間体が生成する。 The first stage is a reaction to induce β-diketone by acyl group introduction reaction.
Examples of the aprotic solvent include toluene and THF.
The concentration of the compound represented by the general formula (Formula 1) in the aprotic solvent is preferably 0.01-1. It is preferable to add almost stoichiometric amount of the compound represented by the general formula (Formula 2).
As the base, LHMDS, KHMDS, NaHMDS, or LDA can be used.
The concentration of the base in the solvent is usually 0.001-1, OM, preferably 0.01-0.1M.
The reaction temperature is usually −78-100 ° C., preferably 20-30 ° C.
The useful intermediate represented by the above general formula (Formula 3) is formed by the reaction at this stage.

第1段階はβ−ジケトン誘導体の閉環反応によりフラボン骨格を形成する反応である。
プロトン性溶媒としては、メタノール、エタノール、水等が挙げられる。
非プロトン性溶媒としては、トルエン、THF等が挙げられる。
プロトン性あるいは非プロトン性溶媒中の一般式（化3）で表される化合物の濃度は好ましくは0．01−1．O Mである。
酸としては、p-トルエンスルホン酸、カンファースルホン酸、トリフルオロ酢酸、塩酸、硫酸を用いることができる。
溶媒中の酸の濃度は通常0．001−1．OM、好ましくは0．01−0．1Mである。
反応温度は通常 0−100℃、好ましくは20−40℃で行われる。
この段階の反応により上記一般式（化4）で表される有用な中間体が生成する The first step is a reaction that forms a flavone skeleton by a ring-closing reaction of a β-diketone derivative.
Examples of the protic solvent include methanol, ethanol, water and the like.
Examples of the aprotic solvent include toluene and THF.
The concentration of the compound represented by the general formula (Formula 3) in a protic or aprotic solvent is preferably 0.01-1. OM.
As the acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid can be used.
The concentration of acid in the solvent is usually 0.001-1. OM, preferably 0.01-0.1M.
The reaction temperature is usually 0-100 ° C, preferably 20-40 ° C.
The useful intermediate represented by the above general formula (Formula 4) is formed by the reaction at this stage.

第3段階は光延反応と呼ばれる反応（Tetrahedron Letters，36，2529（1995））である。
非プロトン性溶媒としては、ベンゼン、トルエン、THF等が挙げられる。
一般式（化4）で表される化合物の少なくとも糖の2位とベンゼン環上の糖の結合位置のオルト位の水酸基が保護されていないことを要する。
非プロトン性溶媒中の一般式（化4）で表される化合物の濃度は好ましくは0．01−0．1Mである。この反応はアゾジカルボン酸アミド又はアゾジカルボン酸エステル及びトリアルキルホスフィン又はトリアリールホスフィンの存在下又はホスホラン類の存在下で行う。アゾジカルポン酸アミドとしては、1，1'−アゾビス（N，N−ジメチルホルムアミド）等が挙げられ、アゾジカルポン酸エステルとしては、ジエチルアゾジカルボキシレート等が挙げられ、トリアルキルホスフィンとしては、トリn−ブチルホスフィン等が挙げられ、トリアリールホスフィンとしては、トリフェニルホスフィン等が挙げられるホスホラン類としては、cyanomethylenetribnutylphosphorane（東京化成製）が挙げられる。
これらは反応物（一般式（化4）で表される化合物）に対して1当量以上用いることが好ましい。反応温度は通常10−100℃、好ましくは20−80℃である。 The third stage is a reaction called Mitsunobu reaction (Tetrahedron Letters, 36, 2529 (1995)).
Examples of the aprotic solvent include benzene, toluene, THF and the like.
In the compound represented by the general formula (Chemical Formula 4), it is necessary that at least the hydroxyl group at the 2-position of the sugar and the ortho-position of the sugar bonding position on the benzene ring is not protected.
The concentration of the compound represented by the general formula (Formula 4) in the aprotic solvent is preferably 0.01 to 0.1M. This reaction is carried out in the presence of azodicarboxylic amide or azodicarboxylic acid ester and trialkylphosphine or triarylphosphine or in the presence of phosphoranes. Examples of the azodicarboxylic acid amide include 1,1′-azobis (N, N-dimethylformamide), examples of the azodicarboxylic acid ester include diethyl azodicarboxylate, and examples of the trialkylphosphine include tri n- Examples thereof include butylphosphine, and examples of the triarylphosphine include cyanomethylenetribnutylphosphorane (manufactured by Tokyo Chemical Industry).
These are preferably used in an amount of 1 equivalent or more based on the reactant (compound represented by the general formula (Formula 4)). The reaction temperature is usually 10-100 ° C, preferably 20-80 ° C.

本発明の製法は、上記の第1段階とその後の第2段階とを主反応として含むことを特徴とするが、これら反応の前後や最終生成物（フラボンC配糖体（Chafuroside））を生成するまでの間に公知の反応を適宜加えてもよい。そのような反応として、（A）水酸基の保護、（E）水酸基の脱保護反応等が挙げられる。これらの反応は本発明の特徴的な部分ではなく、一般的な方法に従って行えばよく、以下その一般的方法を挙げるが、これらに限定されない。
（A）水酸基の保護は、塩基性条件（トリアルキルアミンやK2CO3等の無機塩の存在下）の非プロトン性溶媒中で行うのが一般的である。
（B）水酸基の脱保護反応は、保護基にもよるが、保護基がシリル基やアルキル基等の場合には酸性条件下、ベンジル基等では触媒的水素化条件（例えば、Pd触媒を加えた水素ガス存在下で行う又はF−イオン存在下で行うのが一般的である。 The production method of the present invention is characterized by including the first step and the subsequent second step as main reactions. Before and after these reactions and the final product (flavone C glycoside) is produced. In the meantime, a known reaction may be appropriately added. Examples of such reactions include (A) hydroxyl group protection, (E) hydroxyl group deprotection reaction, and the like. These reactions are not a characteristic part of the present invention, and may be carried out according to a general method. The general methods are listed below, but are not limited thereto.
(A) Protection of the hydroxyl group is generally performed in an aprotic solvent under basic conditions (in the presence of an inorganic salt such as trialkylamine or K 2 CO 3 ).
(B) The deprotection reaction of the hydroxyl group depends on the protecting group, but when the protecting group is a silyl group or an alkyl group, it is acidic, and when the protecting group is a benzyl group, catalytic hydrogenation conditions (for example, a Pd catalyst is added). In general, the reaction is carried out in the presence of hydrogen gas or in the presence of F-ions.

以下、実施例にて本発明を例証するが本発明を限定することを意図するものではない。
製造例１
アルゴン気流下、0 ℃ にて化合物1（4-(benzyloxy)benzoic acid）（2.0 g, 8.77 mmol）の無水塩化メチレン（20mL）溶液に、SOCl2 （0.949 mL，13.2 mmol）および DMF（0.182 mL，3.51 mmol）を加え、同温にて 1 時間撹拌した。反応液を減圧留去し、化合物 2 を得た。
アルゴン気流下、0 ℃ にて 1H-benzo[d][1,2,3]triazole）（1.04 g, 8.77 mmol）の無水塩化メチレン(30mL) 溶液に、Et3N （1.21 mL，8.77 mmol）を0 ℃ にて加え、同温にて 30 分撹拌した。次いで、化合物 2 （8.77 mmol）を0 ℃ にて加え、同温にて 1 時間撹拌した後、室温に昇温し 2 時間撹拌した。反応液を減圧留去し、塩化メチレンーヘキサンから再結晶して化合物3（(1H-benzo[d][1,2,3]triazol-1-yl)(4-(benzyloxy)phenyl)methanone）（1.75 g，60％）を無色結晶として得た。生成物の分析データと反応式を下に示す。
1H NMR (270 MHz, CDCl3): δ 5.20 (s, 2H), 7.3-7.8 (m, 9H), 8.17 (d, 1H, J = 8.2 Hz), 8.30 (d, 2H, J = 9.1 Hz), 8.38 (d, 1H, J = 8.2 Hz).

Figure 2008239513

実施例１ Chafuroside の製造方法 The following examples illustrate the invention but are not intended to limit the invention.
Production Example 1
To a solution of compound 1 (4- (benzyloxy) benzoic acid) (2.0 g, 8.77 mmol) in anhydrous methylene chloride (20 mL) at 0 ° C under an argon stream, SOCl 2 (0.949 mL, 13.2 mmol) and DMF (0.182 mL) 3.51 mmol) and stirred at the same temperature for 1 hour. The reaction solution was distilled off under reduced pressure to obtain Compound 2.
Et 3 N (1.21 mL, 8.77 mmol) was added to a solution of 1H-benzo [d] [1,2,3] triazole) (1.04 g, 8.77 mmol) in anhydrous methylene chloride (30 mL) at 0 ° C under an argon stream. Was added at 0 ° C. and stirred at the same temperature for 30 minutes. Next, Compound 2 (8.77 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for 2 hours. The reaction solution was evaporated under reduced pressure and recrystallized from methylene chloride-hexane to give compound 3 ((1H-benzo [d] [1,2,3] triazol-1-yl) (4- (benzyloxy) phenyl) methanone) (1.75 g, 60%) was obtained as colorless crystals. The analytical data and reaction formula of the product are shown below.
1 H NMR (270 MHz, CDCl 3 ): δ 5.20 (s, 2H), 7.3-7.8 (m, 9H), 8.17 (d, 1H, J = 8.2 Hz), 8.30 (d, 2H, J = 9.1 Hz ), 8.38 (d, 1H, J = 8.2 Hz).
Figure 2008239513
Example 1 Production Method of Chafuroside

アルゴン気流下、0 ℃ にて化合物4（1-(4-(benzyloxy)-2,6-dihydroxy-3-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)ethanone）(200 mg, 0.26 mmol) および imidazole (52 mg, 0.78 mmol) の DMF 溶液 (1.2 mL) に、TBDPS-Cl (0.203 mL, 0.78 mmol) を加え、室温にて 1 時間撹拌した。反応液に飽和NH4Cl aq. を加え、酢酸エチルにて抽出した。抽出液を飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、減圧下溶媒を留去して得られた残査をシリカゲルカラムクロマトグラフィー（hexane：AcOEt = 6：1）にて精製し化合物5（1-(4-(benzyloxy)-6-(tert-butyldiphenylsilyloxy)-2-hydroxy-3-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)ethanone（248 mg, 95%）を無色油状物質として得た。生成物の分析データと反応式を下に示す。
1H NMR (270 MHz, CDCl3, rotamers): δ 1.09, 1.12 (s, 9H), 2.85, 2.91 (s, 3H), 3.5-5.1 (m, 17H), 5.63 (s, 1H), 7.72-6.89 (m, 35H), 13.81, 14.19 (s, 1H).
MS (FAB) m/z 1019 (M+H)+

Figure 2008239513
Compound 4 (1- (4- (benzyloxy) -2,6-dihydroxy-3-((2S, 3R, 5R) -3,4,5-tris (benzyloxy) -6-) at 0 ° C under an argon stream (benzyloxymethyl) -tetrahydro-2H-pyran-2-yl) phenyl) ethanone) (200 mg, 0.26 mmol) and imidazole (52 mg, 0.78 mmol) in DMF solution (1.2 mL) and TBDPS-Cl (0.203 mL, 0.78 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated NH 4 Cl aq. Was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: AcOEt = 6: 1). Compound 5 (1- (4- (benzyloxy) -6- (tert-butyldiphenylsilyloxy) -2-hydroxy-3-((2S, 3R, 5R) -3,4,5-tris (benzyloxy) -6- (benzyloxymethyl ) -tetrahydro-2H-pyran-2-yl) phenyl) ethanone (248 mg, 95%) was obtained as a colorless oil, and the analytical data and reaction formula for the product are shown below.
1 H NMR (270 MHz, CDCl 3 , rotamers): δ 1.09, 1.12 (s, 9H), 2.85, 2.91 (s, 3H), 3.5-5.1 (m, 17H), 5.63 (s, 1H), 7.72- 6.89 (m, 35H), 13.81, 14.19 (s, 1H).
MS (FAB) m / z 1019 (M + H) +
Figure 2008239513

アルゴン気流下、室温にて化合物5 (1.05 g, 1.03 mmol) および PPh3 (810 mg, 3.09 mmol) の THF 溶液 (30 mL) に、benzyl alcohol (0.320 mL, 3.09 mmol) および DEAD (1.3 mL, 3.09 mmol) を加え、室温にて 1 時間撹拌した。反応液を減圧留去して得られた残査をシリカゲルカラムクロマトグラフィー（hexane：AcOEt = 12：1）にて精製し化合物6（1-(2,4-bis(benzyloxy)-6-(tert-butyldiphenylsilyloxy)-3-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)ethanone）（1.07 g, 94％）を無色油状物質として得た。生成物の分析データと反応式を下に示す。
1H NMR (270 MHz, CDCl3, rotamers): δ 1.04, 1.07 (s, 9H), 2.47, 2.59 (s, 3H), 3.5-5.0 (m, 19H), 5.85 (s, 1H), 6.8-7.8 (m, 40H).

Figure 2008239513
To a THF solution (30 mL) of compound 5 (1.05 g, 1.03 mmol) and PPh 3 (810 mg, 3.09 mmol) at room temperature under an argon stream, benzyl alcohol (0.320 mL, 3.09 mmol) and DEAD (1.3 mL, 3.09 mmol) was added and stirred at room temperature for 1 hour. The residue obtained by evaporating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane: AcOEt = 12: 1) to obtain compound 6 (1- (2,4-bis (benzyloxy) -6- (tert -butyldiphenylsilyloxy) -3-((2S, 3R, 5R) -3,4,5-tris (benzyloxy) -6- (benzyloxymethyl) -tetrahydro-2H-pyran-2-yl) phenyl) ethanone) (1.07 g, 94%) as a colorless oil. The analytical data and reaction formula of the product are shown below.
1 H NMR (270 MHz, CDCl 3 , rotamers): δ 1.04, 1.07 (s, 9H), 2.47, 2.59 (s, 3H), 3.5-5.0 (m, 19H), 5.85 (s, 1H), 6.8- 7.8 (m, 40H).
Figure 2008239513

アルゴン気流下、-78 ℃ にて化合物6 (240 mg, 0.216mmol) の THF 溶液 (10 mL) に、KHMDS (0.5 M トルエン溶液) (2.16 mL, 1.08 mmol) を加え、同温にて 1.5 時間撹拌した。次いで製造例1で得た化合物3 (141 mg, 0.432mmol) を加え、同温にて 1 時間撹拌した。0 ℃ に昇温し反応液に飽和NH4Cl aq. を加え、ジエチルエーテルにて抽出した。抽出液を飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、減圧下溶媒を留去して得られた残査をシリカゲルカラムクロマトグラフィー（hexane：AcOEt = 12：1）にて精製し化合物7（1-(4-(benzyloxy)phenyl)-3-(2,4-bis(benzyloxy)-6-(tert-butyldiphenylsilyloxy)-3-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)propane-1,3-dione）（136 mg, 48%）を黄色油状物質として得た。生成物の分析データと反応式を下に示す。
1H NMR (500 MHz, CDCl3, rotamers): δ 0.87, 0.95 (s, 9H, TBDPS), 3.1-5.5 (m, 23H), 6.61, 6.64 (s, 1H), 5.8-8.2 (m, 49H).

Figure 2008239513
Add KHMDS (0.5 M toluene solution) (2.16 mL, 1.08 mmol) to THF solution (10 mL) of compound 6 (240 mg, 0.216 mmol) at -78 ℃ under argon stream, and add 1.5 hours at the same temperature. Stir. Next, Compound 3 (141 mg, 0.432 mmol) obtained in Production Example 1 was added, and the mixture was stirred at the same temperature for 1 hour. The temperature was raised to 0 ° C., saturated NH 4 Cl aq. Was added to the reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: AcOEt = 12: 1). Compound 7 (1- (4- (benzyloxy) phenyl) -3- (2,4-bis (benzyloxy) -6- (tert-butyldiphenylsilyloxy) -3-((2S, 3R, 5R) -3,4,5 -tris (benzyloxy) -6- (benzyloxymethyl) -tetrahydro-2H-pyran-2-yl) phenyl) propane-1,3-dione) (136 mg, 48%) was obtained as a yellow oily substance. The analytical data and reaction formula of the product are shown below.
1 H NMR (500 MHz, CDCl 3 , rotamers): δ 0.87, 0.95 (s, 9H, TBDPS), 3.1-5.5 (m, 23H), 6.61, 6.64 (s, 1H), 5.8-8.2 (m, 49H ).
Figure 2008239513

0 ℃ にて化合物7 (125 mg, 0.095mmol) の THF 溶液 (3 mL) に、TBAF (1.0 M THF 溶液) (0.47mL, 0.474 mmol) を加え、同温にて 30 分撹拌した。次いで製造例1で得た化合物3 (141 mg, 0.432mmol) を加え、同温にて 1 時間撹拌した。0 ℃ に昇温し反応液に飽和NH4Cl aq. を加え、ジエチルエーテルにて抽出した。抽出液を飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥し、減圧下溶媒を留去して得られた残査をシリカゲルカラムクロマトグラフィー（hexane：AcOEt = 10：1）にて精製し化合物8（1-(4-(benzyloxy)phenyl)-3-(2,4-bis(benzyloxy)-6-hydroxy-3-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)propane-1,3-dione）（102 mg, 99%）を黄色油状物質として得た。生成物の分析データと反応式を下に示す。
1H NMR (500 MHz, CDCl3, rotamers): δ 3.0-5.2 (m, 23H), 6.34 (s, 1H), 6.6-7.7 (m, 39H, Ar), 12.76, 12.79 (s, 1H, OH).

Figure 2008239513
TBAF (1.0 M THF solution) (0.47 mL, 0.474 mmol) was added to a THF solution (3 mL) of compound 7 (125 mg, 0.095 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Next, Compound 3 (141 mg, 0.432 mmol) obtained in Production Example 1 was added, and the mixture was stirred at the same temperature for 1 hour. The temperature was raised to 0 ° C., saturated NH 4 Cl aq. Was added to the reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: AcOEt = 10: 1). Compound 8 (1- (4- (benzyloxy) phenyl) -3- (2,4-bis (benzyloxy) -6-hydroxy-3-((2S, 3R, 5R) -3,4,5-tris (benzyloxy ) -6- (benzyloxymethyl) -tetrahydro-2H-pyran-2-yl) phenyl) propane-1,3-dione) (102 mg, 99%) was obtained as a yellow oily substance. The analytical data and reaction formula of the product are shown below.
1 H NMR (500 MHz, CDCl 3 , rotamers): δ 3.0-5.2 (m, 23H), 6.34 (s, 1H), 6.6-7.7 (m, 39H, Ar), 12.76, 12.79 (s, 1H, OH ).
Figure 2008239513

アルゴン気流下、室温にて化合物8 (197 mg, 0.138 mmol) および p-TsOH (1 水和物) (26mg, 0.138 mmol) のトルエン溶液 (10 mL) を、80 ℃ にて 2 時間撹拌した。反応液を減圧留去して得られた残査をシリカゲルカラムクロマトグラフィー（hexane：AcOEt = 5：1）にて精製し化合物9（7-(benzyloxy)-2-(4-(benzyloxy)phenyl)-5-hydroxy-6-((2S,3R,5R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-4H-chromen-4-one）（98 mg, 73％）を無色油状物質として得た。生成物の分析データと反応式を下に示す。
1H NMR (270 MHz, CDCl3, rotamers): δ 3.4-5.4 (m, 19H), 6.39, 6.46, 6.55, 6.61 (s, 2H), 6.8-8.0 (m, 34H), 13.32, 13.39 (s, 1H, OH).

Figure 2008239513
Under a stream of argon, a toluene solution (10 mL) of compound 8 (197 mg, 0.138 mmol) and p-TsOH (monohydrate) (26 mg, 0.138 mmol) was stirred at 80 ° C. for 2 hours. The residue obtained by evaporating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane: AcOEt = 5: 1) to obtain compound 9 (7- (benzyloxy) -2- (4- (benzyloxy) phenyl) -5-hydroxy-6-((2S, 3R, 5R) -3,4,5-tris (benzyloxy) -6- (benzyloxymethyl) -tetrahydro-2H-pyran-2-yl) -4H-chromen-4- one) (98 mg, 73%) was obtained as a colorless oil. The analytical data and reaction formula of the product are shown below.
1 H NMR (270 MHz, CDCl 3 , rotamers): δ 3.4-5.4 (m, 19H), 6.39, 6.46, 6.55, 6.61 (s, 2H), 6.8-8.0 (m, 34H), 13.32, 13.39 (s , 1H, OH).
Figure 2008239513

水素気流下、化合物9 (83 mg, 0.085 mmol) および Pd(OH)2 (7.0mg, 0.051 mmol) の酢酸エチル−メタノール (1:1) 混合溶液トルエン溶液 (4 mL) を、室温にて 12 時間撹拌した。さらに、Pd(OH)2 (7.0mg, 0.051 mmol) を加え、同温にて 4 時間撹拌した。反応液を濾過後、溶媒を減圧留去して化合物10
（5,7-dihydroxy-2-(4-hydroxyphenyl)-6-((2S,3S,5S)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-2-yl)-4H-chromen-4-one）（30 mg）を燈色アモルファスとして得た。生成物の分析データと反応式を下に示す。
1H NMR (270 MHz, CD3OD): δ 3.2-4.2 (m, 6H), 4.7-4.82 (d, 1H), 6.39 (s, 1H), 6.49 (s, 1H), 6.82 (d, 2H, J = 8.6 Hz), 7.73 (d, 2H, J = 8.6 Hz).

Figure 2008239513
Under a hydrogen stream, compound 9 (83 mg, 0.085 mmol) and Pd (OH) 2 (7.0 mg, 0.051 mmol) in ethyl acetate-methanol (1: 1) toluene solution (4 mL) were added at room temperature to 12 Stir for hours. Furthermore, Pd (OH) 2 (7.0 mg, 0.051 mmol) was added, and the mixture was stirred at the same temperature for 4 hours. After filtering the reaction solution, the solvent was distilled off under reduced pressure to remove compound 10
(5,7-dihydroxy-2- (4-hydroxyphenyl) -6-((2S, 3S, 5S) -3,4,5-trihydroxy-6- (hydroxymethyl) -tetrahydro-2H-pyran-2-yl) -4H-chromen-4-one) (30 mg) was obtained as amber amorphous. The analytical data and reaction formula of the product are shown below.
1 H NMR (270 MHz, CD 3 OD): δ 3.2-4.2 (m, 6H), 4.7-4.82 (d, 1H), 6.39 (s, 1H), 6.49 (s, 1H), 6.82 (d, 2H , J = 8.6 Hz), 7.73 (d, 2H, J = 8.6 Hz).
Figure 2008239513

アルゴン気流下、室温にて化合物10 (9.0 mg, 0.021 mmol) および PPh3 (11 mg, 0.042 mmol) の THF 溶液 (1 mL) に、DEAD (0.018 mL, 0.042 mmol) を加え、60 ℃ にて 1 時間撹拌した。反応液を減圧留去して得られた残査をシリカゲルカラムクロマトグラフィー（CHCl3：MeOH = 8：1）にて精製し化合物11 (Chafuroside)（2.0 mg, 23％）を無色アモルファスとして得た。生成物の分析データと反応式を下に示す。
1H NMR (500 MHz, DMSO-d6, 300K): δ 3.21 (ddd, 1H, J = 9.2, 5.7, 2.3 Hz), 3.36 (td, 1H, J = 9.2, 5.4 Hz), 3.40 (dt, 1H, J = 12.2, 5.7 Hz), 3.64 (ddd, 1H, J = 12.2, 5.7, 2.3 Hz), 3.84 (dt, 1H, J = 9.2, 5.1 Hz), 4.42 (t, 1H, J = 5.7 Hz), 4.59 (dd, 1H, J = 5.1, 3.0 Hz), 4.99 (d, 1H, J = 5.4 Hz), 5.07 (d, 1H, J = 3.0 Hz), 5.37 (d, 1H, J = 5.1 Hz), 6.75 (s, 1H), 6.84 (s, 1H), 6.92 (d, 2H, J = 9.2 Hz), 7.95 (d, 2H, J = 9.2 Hz), 10.35 (brs, 1H), 13.53 (s, 1H).
13C NMR (500 MHz, DMSO-d6, 300K): δ 60.9, 67.3, 71.2, 78.8, 87.5, 90.2, 102.8, 105.0, 111.3, 115.9, 120.9, 128.5, 157.0, 158.4, 161.3, 164.0, 166.3, 182.3.
MS (FAB) m/z 415 (M+H)+; HRMS calcd for C21H19O9 (M+H)+ 415.1029, found 415.1032.

Figure 2008239513
To a THF solution (1 mL) of compound 10 (9.0 mg, 0.021 mmol) and PPh 3 (11 mg, 0.042 mmol) at room temperature under an argon stream, add DEAD (0.018 mL, 0.042 mmol) at 60 ° C. Stir for 1 hour. The residue obtained by evaporating the reaction solution under reduced pressure was purified by silica gel column chromatography (CHCl 3 : MeOH = 8: 1) to obtain Compound 11 (Chafuroside) (2.0 mg, 23%) as a colorless amorphous substance. . The analytical data and reaction formula of the product are shown below.
1 H NMR (500 MHz, DMSO-d 6 , 300K): δ 3.21 (ddd, 1H, J = 9.2, 5.7, 2.3 Hz), 3.36 (td, 1H, J = 9.2, 5.4 Hz), 3.40 (dt, 1H, J = 12.2, 5.7 Hz), 3.64 (ddd, 1H, J = 12.2, 5.7, 2.3 Hz), 3.84 (dt, 1H, J = 9.2, 5.1 Hz), 4.42 (t, 1H, J = 5.7 Hz ), 4.59 (dd, 1H, J = 5.1, 3.0 Hz), 4.99 (d, 1H, J = 5.4 Hz), 5.07 (d, 1H, J = 3.0 Hz), 5.37 (d, 1H, J = 5.1 Hz) ), 6.75 (s, 1H), 6.84 (s, 1H), 6.92 (d, 2H, J = 9.2 Hz), 7.95 (d, 2H, J = 9.2 Hz), 10.35 (brs, 1H), 13.53 (s , 1H).
13 C NMR (500 MHz, DMSO-d 6 , 300K): δ 60.9, 67.3, 71.2, 78.8, 87.5, 90.2, 102.8, 105.0, 111.3, 115.9, 120.9, 128.5, 157.0, 158.4, 161.3, 164.0, 166.3, 182.3.
MS (FAB) m / z 415 (M + H) + ; HRMS calcd for C 21 H 19 O 9 (M + H) + 415.1029, found 415.1032.
Figure 2008239513

Claims (2)

非プロトン性溶媒中で下式（化1）
Figure 2008239513
 （式中、R 1 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R2 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物と下式（化2）
Figure 2008239513
（式中、R3 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R4 はベンツトリアゾール基、イミダゾール基、ハロゲン原子、エステル基を表す。）で表される化合物とを塩基存在下で反応させる第1段階、及びプロトン性あるいは非プロトン性溶媒中で下式（化3）
Figure 2008239513
（式中、R5 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 6 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R7 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物を酸の存在下で反応させる第2段階、及び非プロトン性溶媒中で下式（化4）
Figure 2008239513
 （式中、R8 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子を表し、R 9 は水酸基、保護された水酸基、エーテル基又はエステル基、ハロゲン原子を表し、R10 はそれぞれ同じであっても異なってもよく水素原子又はアルキル基、アシル基、水酸基、保護された水酸基、ハロゲン原子、グルコース等の糖類を表す。）で表される化合物を、アゾジカルボン酸アミド又はアゾジカルボン酸エステル及びトリアルキルホスフィン又はトリアリールホスフィンの存在下又はホスホラン類の存在下で反応させる第3段階を含む下式（化5）
Figure 2008239513
 で表される Chafuroside 等のフラボン類の製法。
In the aprotic solvent (Formula 1)
Figure 2008239513
 (In the formula, R 1 represents a hydroxyl group, a protected hydroxyl group, an ether group or an ester group, and a halogen atom, and R 2 may be the same or different from each other, and may be a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected group. And a compound represented by the following formula (Chemical formula 2):
Figure 2008239513
(Wherein R 3 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 4 represents a benztriazole group, an imidazole group or a halogen atom; Represents the ester group.) In the first step of reacting with the compound represented by the base in the presence of a base, and in the protic or aprotic solvent:
Figure 2008239513
(Wherein R 5 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 6 represents a hydroxyl group, a protected hydroxyl group or an ether group; Or an ester group and a halogen atom, and R 7 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, or a sugar such as glucose). A second step in which the compound represented is reacted in the presence of an acid, and in an aprotic solvent:
Figure 2008239513
 (Wherein R 8 may be the same or different and each represents a hydrogen atom, an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group or a halogen atom; R 9 represents a hydroxyl group, a protected hydroxyl group or an ether group; Or an ester group and a halogen atom, and R 10 may be the same or different and each represents a hydrogen atom or an alkyl group, an acyl group, a hydroxyl group, a protected hydroxyl group, a halogen atom, or a sugar such as glucose). The following formula comprising a third step in which the compound represented is reacted in the presence of an azodicarboxylic amide or azodicarboxylic acid ester and a trialkylphosphine or triarylphosphine or in the presence of phosphoranes (Formula 5)
Figure 2008239513
 The production method of flavones such as Chafuroside.
前記一般式（化4）で表される化合物が下記の化合物である請求項１に記載の製法。
Figure 2008239513
（式中、水酸基は保護されていてもよい。） The process according to claim 1, wherein the compound represented by the general formula (Formula 4) is the following compound.
Figure 2008239513
(In the formula, the hydroxyl group may be protected.)
JP2007079311A 2007-03-26 2007-03-26 New method for producing chafuroside based on efficient flavone construction Pending JP2008239513A (en)

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US20040059100A1 (en) * 2001-02-01 2004-03-25 Herwig Buchholz Process for the preparation of flavone derivatives
JP2005289888A (en) * 2004-03-31 2005-10-20 Suntory Ltd Preparation method of flavone c glycoside derivative
JP2005314260A (en) * 2004-04-28 2005-11-10 Japan Science & Technology Agency Method for producing flavone c glycoside
JP2006008626A (en) * 2004-06-28 2006-01-12 Daiichi Asubio Pharma Co Ltd Method for producing flavone derivative, flavone derivative and medicinal composition including the same
JP2006176407A (en) * 2003-04-18 2006-07-06 Daiichi Asubio Pharma Co Ltd New flavone derivative, method for producing the same and medicine composition containing the same

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JP2006176407A (en) * 2003-04-18 2006-07-06 Daiichi Asubio Pharma Co Ltd New flavone derivative, method for producing the same and medicine composition containing the same
JP2005289888A (en) * 2004-03-31 2005-10-20 Suntory Ltd Preparation method of flavone c glycoside derivative
JP2005314260A (en) * 2004-04-28 2005-11-10 Japan Science & Technology Agency Method for producing flavone c glycoside
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010076879A1 (en) * 2009-01-03 2010-07-08 静岡県公立大学法人 Sulfated c-glycoside, method for isolating same and method for synthesizing same
JP5597142B2 (en) * 2009-01-03 2014-10-01 静岡県公立大学法人 Sulfated C-glycoside, isolation method and synthesis method thereof

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