JP2021059511A - Method for Producing Dimer Compound of Cinnamic Acid Derivative - Google Patents
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本発明は、フェルラ酸などの桂皮酸誘導体を二量化する方法に関する。 The present invention relates to a method for dimerizing a cinnamic acid derivative such as ferulic acid.
フェルラ酸は、植物の細胞壁などに存在する桂皮酸誘導体であり、リグニンの前駆体である。一方、フェルラ酸の二量体の一つはポアシン酸(８，５−ジフェルラ酸)と呼ばれ、サトウキビの非加食部から抽出され発見された化合物で、β−１，３−グルカン生成阻害作用を有することから、広い抗菌スペクトルを有し、強力な抗真菌活性を有することが知られている(非特許文献１)。農作物に感染する病原菌の生育を抑え、従来の硫酸銅を含む農薬に比べ抗菌作用が１０倍強いため、植物由来の物質を使った環境汚染リスクの低い農薬として、実用化に向けた研究が進められている。 Ferulic acid is a cinnamic acid derivative present in the cell wall of plants and is a precursor of lignin. On the other hand, one of the dimers of ferulic acid is called poacic acid (8,5-diferulic acid), which is a compound discovered from the non-eating part of sugar cane and inhibits β-1,3-glucan production. It is known to have a broad antibacterial spectrum and strong antifungal activity because it has an action (Non-Patent Document 1). Since it suppresses the growth of pathogens that infect crops and has 10 times stronger antibacterial action than conventional pesticides containing copper sulfate, research is underway for practical use as pesticides that use plant-derived substances and have a low risk of environmental pollution. Has been done.
このように植物農薬としの使用が期待される二量体化合物であるポアシン酸を製造する方法として、従来、酸素を使用した酸化反応(非特許文献２：([化４]参照)と、酵素を使用した酸化反応(非特許文献３：([化５]参照))により、フェルラ酸エチルを二量化した後にアルカリ加水分解して製造する方法が行われている。 Conventionally, as a method for producing poacic acid, which is a dimeric compound expected to be used as a plant pesticide, an oxidation reaction using oxygen (Non-Patent Document 2: (see [Chemical Formula 4]) and an enzyme (Non-Patent Document 3: (see [Chemical Formula 5])), a method of dimerizing ethyl ferlate and then alkaline hydrolysis is performed.
非特許文献２には、フェニル酸エチルを出発原料として、アセトニトリル溶媒中で、等量の塩化銅(２価)とテトラメチルエチレンジアミンの存在下、酸素を吹き込み、好気性酸化カップリング反応により６つのフェニル酸エチル二量体を合成し、クロマトグラフィーでそれぞれ精製したことが記載されている。また、非特許文献３には、フェルラ酸エチルを、過酸化水素−尿素複合体の存在下、ペルオキシダーゼを用いて脱水二量化することにより、主に８−５結合ジフェルラ酸エチルであるフェルラ酸エチル二量体を合成できることが記載されている。どちらの場合も、合成した８，５−ジフェルラ酸エチルからアルカリ加水分解により、フェルラ酸二量体であるポアシン酸を製造する。
In
従来のポアシン酸の合成法においては、次のような問題点が存在する。
酸素を使用した酸化反応では、選択率が十分でないため、ポアシン酸中間体の収率が２２％程度と低く、さらに、副生成物の種類が多く複雑なため、単離精製に手間がかかる。
また、酵素を使用した酸化反応では、ポアシン酸中間体の収率は５０％程度と高いものの、高価な酵素の回収、再利用が難しいためコストが高くつき、また、酵素の基質特異性により対応する基質がフェルラ酸に限られること、アセトン中で過酸化水素を使用するため、副生成物として爆発性の過酸化アセトンを生成しやすいという難点があった。
The conventional method for synthesizing poacidic acid has the following problems.
In the oxidation reaction using oxygen, the selectivity is not sufficient, so that the yield of the poacidic acid intermediate is as low as about 22%, and since there are many kinds of by-products and it is complicated, it takes time to isolate and purify.
Further, in the oxidation reaction using an enzyme, although the yield of the poacic acid intermediate is as high as about 50%, the cost is high because it is difficult to recover and reuse the expensive enzyme, and the substrate specificity of the enzyme can be used. Since the substrate to be used is limited to ferulic acid and hydrogen peroxide is used in acetone, there are drawbacks that explosive acetone peroxide is easily produced as a by-product.
本発明は、従来技術の欠点を改善するために、安価な触媒を用いても副生成物が少なく、収率よく桂皮酸誘導体を二量化する方法を提供することをその課題とする。そして、得られた桂皮酸誘導体の二量化体を加水分解したものは、ポアシン酸と同様の抗真菌薬として使用することができる。 An object of the present invention is to provide a method for dimerizing a cinnamic acid derivative in a high yield with a small amount of by-products even if an inexpensive catalyst is used in order to improve the drawbacks of the prior art. Then, the obtained dimer of the cinnamic acid derivative hydrolyzed can be used as an antifungal agent similar to poacic acid.
発明者らは、鋭意研究を重ね、触媒として安価なヨウ素および酸化剤として過酸化水素を用いるか、または過ヨウ素酸の存在下で桂皮酸誘導体を反応させることにより、所望の二量体化合物を低コストで比較的高収率で得ることができる合成法を開発した。この方法を用いると、従来では不可能だった二種類の桂皮酸誘導体を原料としたクロスカップリング体の合成も可能となる。 The inventors have conducted extensive research to obtain the desired dimeric compound by using inexpensive iodine as a catalyst and hydrogen peroxide as an oxidant, or by reacting a cinnamic acid derivative in the presence of periodic acid. We have developed a synthetic method that can be obtained at low cost and in a relatively high yield. By using this method, it is possible to synthesize a cross-coupling product using two kinds of cinnamic acid derivatives as raw materials, which was impossible in the past.
本発明は、下記(１)〜(１１)の桂皮酸誘導体の二量体化合物の製造方法に関するものである。
（１）フェニル基に少なくとも一つの水酸基もしくはアルコキシ基を持つ桂皮酸誘導体を出発原料とし、触媒としてヨウ素および酸化剤として過酸化水素を用いるか、または過ヨウ素酸の存在下で二量化反応させることを特徴とする、桂皮酸誘導体の二量体化合物の製造方法。
（２）前記フェニル基に少なくとも一つの水酸基もしくはアルコキシ基を持つ桂皮酸誘導体が、[式１]および[式２]の化合物であり、製造される桂皮酸誘導体の二量体化合物が[式３]の化合物である、上記(１)に記載の桂皮酸誘導体の二量体化合物の製造方法。
（３）前記[式１]および[式２]において、Ｒ1とＲ4が同じで、Ｒ2がＨ、Ｒ3がＯＨであり、前記出発原料が１種類の桂皮酸誘導体である、上記(１)または(２)に記載の桂皮酸誘導体の二量体化合物の製造方法。
（４）前記[式１]および[式２]において、Ｒ1とＲ4がＯＭｅで、Ｒ2がＨ、Ｒ3がＯＨであり、前記出発原料が１種類のフェルラ酸であり、製造される二量体化合物がポアシン酸である、上記(１)または(２)に記載の桂皮酸誘導体の二量体化合物の製造方法。
（５）前記[式１]および[式２]において、Ｒ1とＲ4がＨで、Ｒ2がＨ、Ｒ3がＯＨであり、前記出発原料が１種類のクマル酸であり、製造される二量体化合物がポアシン酸類似体である、上記(１)または(２)に記載の桂皮酸誘導体の二量体化合物の製造方法。
The present invention relates to the following methods (1) to (11) for producing a dimer compound of a cinnamic acid derivative.
(1) Using a cinnamic acid derivative having at least one hydroxyl group or an alkoxy group in a phenyl group as a starting material, iodine as a catalyst and hydrogen peroxide as an oxidizing agent, or a dimerization reaction in the presence of periodic acid. A method for producing a dimer compound of a katsura acid derivative, which comprises the above.
(2) The cinnamic acid derivative having at least one hydroxyl group or alkoxy group in the phenyl group is the compound of [Formula 1] and [Formula 2], and the dimer compound of the cinnamic acid derivative produced is [Formula 3]. ], The method for producing a dimer compound of the cinnamic acid derivative according to (1) above.
(3) In the above [Formula 1] and [Formula 2], R 1 and R 4 are the same, R 2 is H, R 3 is OH, and the starting material is one kind of cinnamic acid derivative. The method for producing a dimer compound of a cinnamic acid derivative according to (1) or (2).
(4) In the above [Formula 1] and [Formula 2], R 1 and R 4 are OMe, R 2 is H, R 3 is OH, and the starting material is one kind of ferulic acid. The method for producing a dimer compound of a cinnamic acid derivative according to (1) or (2) above, wherein the dimer compound is poacic acid.
(5) In the above [Formula 1] and [Formula 2], R 1 and R 4 are H, R 2 is H, R 3 is OH, and the starting material is one kind of coumaric acid. The method for producing a dimer compound of a cinnamic acid derivative according to the above (1) or (2), wherein the dimer compound is a poacidic acid analog.
（６）前記出発原料が２種類の桂皮酸誘導体である、上記(１)または(２)に記載の桂皮酸誘導体の二量体化合物の製造方法。
（７）前記[式１]および[式２]において、Ｒ1とＲ4がＯＭｅで、Ｒ2がＯＭｅ、Ｒ3がＯＨであり、前記出発原料がフェルラ酸とシナピン酸であり、製造される二量体化合物がポアシン酸類似体である、上記(１)または(２)に記載の桂皮酸誘導体の二量体化合物の製造方法。
（８）前記製造方法をアセトニトリル溶媒中で行なう、上記(１)ないし(７)のいずれかに記載の桂皮酸誘導体の二量体化合物の製造方法。
（９）前記製造方法を加熱条件下で行なう上記(１)ないし(８)のいずれかに記載の桂皮酸誘導体の二量体化合物の製造方法。
（１０）前記製造方法を脱水剤の存在下で行なう、上記(１)ないし(９)のいずれかに記載の桂皮酸誘導体の二量体化合物の製造方法。
（１１）前記出発原料の桂皮酸誘導体をエチルエステル化する工程を含む、上記(１)ないし(１０)のいずれかに記載の桂皮酸誘導体の二量体化合物の製造方法。
(6) The method for producing a dimer compound of a cinnamic acid derivative according to (1) or (2) above, wherein the starting material is two types of cinnamic acid derivatives.
(7) In the above [Formula 1] and [Formula 2], R 1 and R 4 are OMe, R 2 is OMe, R 3 is OH, and the starting materials are ferulic acid and sinapinic acid. The method for producing a dimer compound of a cinnamic acid derivative according to (1) or (2) above, wherein the dimer compound is a poacinic acid analog.
(8) The method for producing a dimer compound of a cinnamic acid derivative according to any one of (1) to (7) above, wherein the production method is carried out in an acetonitrile solvent.
(9) The method for producing a dimer compound of a cinnamic acid derivative according to any one of (1) to (8) above, wherein the production method is carried out under heating conditions.
(10) The method for producing a dimer compound of a cinnamic acid derivative according to any one of (1) to (9) above, wherein the production method is carried out in the presence of a dehydrating agent.
(11) The method for producing a dimer compound of a cinnamic acid derivative according to any one of (1) to (10) above, which comprises a step of ethyl esterifying the cinnamic acid derivative as a starting material.
また、本発明は、下記(１２)、(１３)の新規ポアシン酸類似体化合物、および下記(１４)の抗真菌剤に関するものである。
（１２）下記[式８]で表される新規ポアシン酸類似体化合物
(12) A novel poacidic acid analog compound represented by the following [Formula 8]
本発明によれば、安価なヨウ素を触媒として用いて、低コストで収率がよく、副生成物の産生が少ないことから精製も簡便である、所望の桂皮酸誘導体の二量体化合物の合成法を提供できる。
また、従来では不可能だった二種類の桂皮酸誘導体を原料としたクロスカップリング体の合成も可能となり、酵素のような基質特異性がないため、基質の範囲が広く基質適用性が広いことから、天然には存在しない桂皮酸誘導体の二量体化合物を合成することができる。
According to the present invention, the synthesis of a dimer compound of a desired cinnamic acid derivative, which is easy to purify because of low cost, good yield, and low production of by-products, using inexpensive iodine as a catalyst. Can provide law.
In addition, it is possible to synthesize cross-coupling compounds using two types of cinnamic acid derivatives, which was not possible in the past, and because there is no substrate specificity like enzymes, the range of substrates is wide and the applicability of substrates is wide. Therefore, a dimer compound of a cinnamic acid derivative that does not exist in nature can be synthesized.
本発明では、フェニル基に少なくとも一つの水酸基もしくはアルコキシ基を持つ桂皮酸誘導体を出発原料とし、桂皮酸誘導体の二量体化合物体を製造する方法において、触媒としてヨウ素および酸化剤として過酸化水素を用いるか、または過ヨウ素酸を用いるものである。 In the present invention, in a method for producing a dimer compound of a katsura acid derivative using a katsura acid derivative having at least one hydroxyl group or an alkoxy group in a phenyl group as a starting material, iodine is used as a catalyst and hydrogen peroxide is used as an oxidizing agent. It is used or uses periodic acid.
原料として用いるフェニル基に少なくとも一つの水酸基もしくはアルコキシ基を持つ桂皮酸誘導体は、上記[式１]および[式２]に示す構造であれば特に限定されないが、例えば、クマル酸、カフェ酸、フェルラ酸、シナピン酸、などが挙げられる。これらの純度は特に制限されず、粗精製物のまま原料として用いることができる。また、原料を含水状態で供給してもよく、乾燥工程を経て供給してもよい。
桂皮酸誘導体は通常、二量化工程の前にエステル化する。例えば、塩化アセチルとエタノールとを反応させて得られるエタノール−ＨＣｌにより、フェルラ酸をエチルエステル化する。
The cinnamic acid derivative having at least one hydroxyl group or an alkoxy group in the phenyl group used as a raw material is not particularly limited as long as it has the structures shown in the above [Formula 1] and [Formula 2], and is, for example, coumaric acid, caffeic acid, and ferulic acid. Acids, sinamic acid, etc. may be mentioned. The purity of these is not particularly limited, and the crude product can be used as a raw material as it is. Further, the raw material may be supplied in a water-containing state, or may be supplied after a drying step.
Cinnamic acid derivatives are usually esterified prior to the dimerization step. For example, ferulic acid is ethyl esterified with ethanol-HCl obtained by reacting acetyl chloride with ethanol.
次いで、エステル化された桂皮酸誘導体の二量化反応を有機溶媒中で行う。使用する有機溶媒は、例えば、アセトニトリル、ジメチルスルホキシド、スルホラン、メタノール、エタノール、プロパノール、ブタノール、ペンタノール、ヘキサノールなどが挙げられ、アシトニトリルが好ましい。 Then, the dimerization reaction of the esterified cinnamic acid derivative is carried out in an organic solvent. Examples of the organic solvent used include acetonitrile, dimethyl sulfoxide, sulfolane, methanol, ethanol, propanol, butanol, pentanol, hexanol and the like, and acidonitrile is preferable.
触媒としてヨウ素および酸化剤として過酸化水素を用いる場合には、ヨウ素は固体のままもしくはあらかじめ適当な溶媒に溶解させて加えることができる。触媒の使用量は、原料である桂皮酸誘導体に対して０.１等量であり、好ましくは０.０１〜０.５、より好ましくは０.０５〜０.２である。酸化剤としての過酸化水素は、過酸化水素水溶液を用いることもできるが、炭酸ナトリウムもしくは尿素の会合体として用いることが好ましい。酸化剤の使用量は、１〜１０当量が好ましいが、より好ましくは１.５〜２.５等量である。 When iodine is used as a catalyst and hydrogen peroxide is used as an oxidizing agent, iodine can be added as a solid or dissolved in a suitable solvent in advance. The amount of the catalyst used is 0.1 equivalent with respect to the cinnamic acid derivative as a raw material, preferably 0.01 to 0.5, and more preferably 0.05 to 0.2. As the hydrogen peroxide as an oxidizing agent, an aqueous hydrogen peroxide solution can be used, but it is preferable to use it as an aggregate of sodium carbonate or urea. The amount of the oxidizing agent used is preferably 1 to 10 equivalents, more preferably 1.5 to 2.5 equivalents.
また、過ヨウ素酸の存在下で二量化反応させる場合には、過ヨウ素酸の使用量は、１〜１０当量が好ましいが、より好ましくは１.５〜３等量である。
触媒としてヨウ素を用いる場合も、過ヨウ素酸の存在下で反応させる場合もどちらも脱水剤の存在下で行うのが好ましい。脱水剤としては特に特定されないが、ゼオライト、シリカゲル、硫酸マグネシウム、硫酸カルシウム、硫酸カリウム、硫酸ナトリウムが好ましい。
When the dimerization reaction is carried out in the presence of periodic acid, the amount of periodic acid used is preferably 1 to 10 equivalents, more preferably 1.5 to 3 equivalents.
Both when iodine is used as a catalyst and when the reaction is carried out in the presence of periodic acid, it is preferable to carry out in the presence of a dehydrating agent. The dehydrating agent is not particularly specified, but zeolite, silica gel, magnesium sulfate, calcium sulfate, potassium sulfate and sodium sulfate are preferable.
反応温度は，４０℃〜８０℃、中でも５０℃〜６０℃の範囲とするのがよい。反応温度がこれより低いと反応速度が遅くなるし、また、これより高いと生成した桂皮酸誘導体の環化二量体中間体が分解する。反応時間は、反応温度にもよるが一般に１〜３時間である。 The reaction temperature is preferably in the range of 40 ° C. to 80 ° C., particularly 50 ° C. to 60 ° C. If the reaction temperature is lower than this, the reaction rate will be slower, and if it is higher than this, the cyclized dimer intermediate of the produced cinnamic acid derivative will be decomposed. The reaction time is generally 1 to 3 hours, although it depends on the reaction temperature.
生成した二量化中間体をクロマトグラフィーで精製してから、アルカリ加水分解することにより、所望の桂皮酸誘導体の二量体化合物を得ることができる。
アルカリ加水分解は、例えば、水酸化ナトリウムの存在下、１ＭＰａの圧力下９０℃程度に加熱することにより行う。
A dimer compound of a desired cinnamic acid derivative can be obtained by purifying the produced dimerization intermediate by chromatography and then alkaline hydrolysis.
Alkaline hydrolysis is carried out, for example, by heating to about 90 ° C. under a pressure of 1 MPa in the presence of sodium hydroxide.
本発明の方法の製造方法の一例を以下に示す。
次に、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例により何ら限定されるものではない。 Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
（実施例１）＜過ヨウ素酸ナトリウムを使用したフェルラ酸環化二量体の合成＞
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、過ヨウ素酸ナトリウム(ナカライテスク)６０ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍｌと純水０.５ｍｌを加えた。２時間後、反応液に純水１０ｍＬと酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が７.５ｍｇ(収率７.５％(最大収率５０％))で得られた。
(Example 1) <Synthesis of ferulic acid cyclized dimer using sodium periodate>
To a glass tube having an internal volume of 10 mL, 50 mg of ethyl ferurate (Tokyo Chemical Industry), 60 mg of sodium periodate (Nacalai Tesque), 0.5 ml of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) and 0.5 ml of pure water were added. After 2 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution, and the mixture was separated and washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained in 7.5 mg (yield 7.5% (maximum yield 50%)).
（実施例２）＜ヨウ素と３０％過酸化水素水を使用したフェルラ酸環化二量体の合成＞
（実地例２−１）
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、３０％過酸化水素水溶液(富士フィルム和光純薬)４７μｌ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。オイルバスを使用し７０℃に加温し、ヨウ素(富士フィルム和光純薬)５.６ｍｇを加え撹拌した。４時間後室温に戻し、反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が７.５ｍｇ(収率７.５％(最大収率５０％))で得られた。
(Example 2) <Synthesis of ferulic acid cyclized dimer using iodine and 30% hydrogen peroxide solution>
(Practical example 2-1)
To a glass tube having an internal volume of 10 mL, 50 mg of ethyl ferurate (Tokyo Chemical Industry), 47 μl of a 30% hydrogen peroxide aqueous solution (Fuji Film Wako Pure Chemical Industries, Ltd.), and 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) were added. It was heated to 70 ° C. using an oil bath, 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred. After 4 hours, the temperature was returned to room temperature, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution to stop the reaction, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained in 7.5 mg (yield 7.5% (maximum yield 50%)).
（実施例２−２）
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、３０％過酸化水素水溶液(富士フィルム和光純薬)８７μｌ、炭酸ナトリウム２.３ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。この混合溶液にヨウ素(富士フィルム和光純薬)５.６ｍｇを加え、室温で３時間撹拌した。反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が１１.９ｍｇ(収率１２％(最大収率５０％))で得られた。
(Example 2-2)
50 mg of ethyl ferrate (Tokyo Chemical Industry), 87 μl of 30% hydrogen peroxide aqueous solution (Fuji Film Wako Pure Chemical Industries, Ltd.), 2.3 mg of sodium carbonate, 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) in a glass tube with an internal volume of 10 mL. Was added. 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to this mixed solution, and the mixture was stirred at room temperature for 3 hours. To stop the reaction, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained at 11.9 mg (yield 12% (maximum yield 50%)).
（実施例３）＜ヨウ素と過炭酸ナトリウムを使用したフェルラ酸環化二量体の合成＞
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、過炭酸ナトリウム(アルドリッチ)３０ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。この混合溶液にヨウ素(富士フィルム和光純薬)５.６ｍｇを加え、室温で３時間撹拌した。反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が１６.５ｍｇ(収率１７％(最大収率５０％))で得られた。
(Example 3) <Synthesis of ferulic acid cyclized dimer using iodine and sodium percarbonate>
To a glass tube having an internal volume of 10 mL, 50 mg of ethyl ferurate (Tokyo Chemical Industry), 30 mg of sodium percarbonate (Aldrich), and 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) were added. 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to this mixed solution, and the mixture was stirred at room temperature for 3 hours. To stop the reaction, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained at 16.5 mg (yield 17% (maximum yield 50%)).
（実施例４）＜ヨウ素と過酸化水素尿素を使用したフェルラ酸環化二量体の合成＞
（実施例４−１）
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、過酸化水素尿素(シグマアルドリッチ)３５ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。オイルバスを使用し７０℃に加温し、ヨウ素(富士フィルム和光純薬)５.６ｍｇを加え、撹拌した。５時間後室温に戻し、反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が１１.６ｍｇ(収率１２％(最大収率５０％))で得られた。
(Example 4) <Synthesis of ferulic acid cyclized dimer using iodine and urea hydrogen peroxide>
(Example 4-1)
To a glass tube having an internal volume of 10 mL, 50 mg of ethyl ferurate (Tokyo Chemical Industry), 35 mg of urea hydrogen peroxide (Sigma-Aldrich), and 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) were added. It was heated to 70 ° C. using an oil bath, 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred. After 5 hours, the temperature was returned to room temperature, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution to stop the reaction, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained at 11.6 mg (yield 12% (maximum yield 50%)).
（実施例４−２）
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、過酸化水素尿素(シグマアルドリッチ)３５ｍｇ、炭酸ナトリウム２.１ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。この混合溶液にヨウ素(富士フィルム和光純薬)５.６ｍｇを加え、室温で３時間撹拌した。反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が１５.７ｍｇ(収率１６％(最大収率５０％))で得られた。
(Example 4-2)
To a glass tube having an internal volume of 10 mL, 50 mg of ethyl ferurate (Tokyo Chemical Industry), 35 mg of urea hydrogen peroxide (Sigma-Aldrich), 2.1 mg of sodium carbonate, and 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) were added. 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to this mixed solution, and the mixture was stirred at room temperature for 3 hours. To stop the reaction, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained in 15.7 mg (yield 16% (maximum yield 50%)).
（実施例４−３）
内容積１０ｍＬのガラス管にフェルラ酸エチル(東京化成工業)を５０ｍｇ、過酸化水素尿素(シグマアルドリッチ)３５ｍｇ、４Åモレキュラーシーブ(ナカライテスク)２０ｍｇ、アセトニトリル(富士フィルム和光純薬)０.５ｍＬを加えた。オイルバスを使用し５０℃に加温し、ヨウ素(富士フィルム和光純薬)５.６ｍｇを加え、撹拌した。４時間後室温に戻し、反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ポアシン酸前駆体である環化二量体中間体が２５.２ｍｇ(収率２５％(最大収率５０％))で得られた。
(Example 4-3)
Add 50 mg of ethyl ferulate (Tokyo Chemical Industry), 35 mg of urea hydrogen peroxide (Sigma-Aldrich), 20 mg of 4Å molecular sieve (Nacalai Tesque), and 0.5 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries) to a glass tube with an internal volume of 10 mL. It was. It was heated to 50 ° C. using an oil bath, 5.6 mg of iodine (Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and the mixture was stirred. After 4 hours, the temperature was returned to room temperature, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution to stop the reaction, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), the ring which is a poacic acid precursor was used. The chemical dimer intermediate was obtained in 25.2 mg (yield 25% (maximum yield 50%)).
上記実施例１〜４の結果をまとめたものが表１である。
（実施例５）＜ヨウ素と過炭酸ナトリウムを用いたクマル酸環化二量体の合成＞
内容積１０ｍＬのガラス管にクマル酸エチルを１００ｍｇ、過炭酸ナトリウム(アルドリッチ)１２ｍｇ、アセトニトリル(富士フィルム和光純薬)１.０ｍＬ、ヨウ素５.６ｍｇを加えた他は実施例３と同様に反応を行ない、後処理を行なった。その結果、クマル酸環化二量体中間体が４.３ｍｇ(収率２.１％(最大収率５０％))で得られた。製造方法を以下に示す。
The reaction was carried out in the same manner as in Example 3 except that 100 mg of ethyl coumarate, 12 mg of sodium percarbonate (Aldrich), 1.0 mL of acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) and 5.6 mg of iodine were added to a glass tube having an internal volume of 10 mL. It was done and post-processing was done. As a result, a coumaric acid cyclized dimer intermediate was obtained in an amount of 4.3 mg (yield 2.1% (maximum yield 50%)). The manufacturing method is shown below.
（実施例６）＜ヨウ素と過酸化水素尿素を用いたファルラ酸とシナピン酸のヘテロ環化体の合成＞
内容積１０ｍＬのガラス管にシナピン酸エチルを７５ｍｇ、ヨウ素(富士フィルム和光純薬)５.６ｍｇ、過酸化水素尿素(シグマアルドリッチ)４２ｍｇ、４Åモレキュラーシーブ(ナカライテスク)２０ｍｇ、アセトニトリル(富士フィルム和光純薬)０.２ｍＬを加えた。オイルバスを使用し５０℃に加温し撹拌を行い、０.３ｍＬに溶かしたフェルラ酸エチル(東京化成工業)５０ｍｇを２０分毎に０.１ｍＬずつこの混合溶液に滴下した。２時間３０分後、室温に戻し、反応停止のため反応液に１０％チオ硫酸ナトリウム水溶液(キシダ化学)３ｍＬを加え５分間撹拌した。酢酸エチル(キシダ化学)１０ｍＬを加え、分液処理を行ったのち、飽和食塩水をもちい洗浄した。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)をヘキサンと酢酸エチル(３：１から１：１にヘキサンと酢酸エチルの比率を変更した)を使用して精製を行った結果、ヘテロ環化二量体中間体が４８.４ｍｇ(収率４６％)で得られた。
(Example 6) <Synthesis of heterocyclic compounds of farulic acid and sinapic acid using iodine and urea hydrogen peroxide>
Ethyl sinapinate 75 mg, iodine (Fuji Film Wako Pure Chemical Industries, Ltd.) 5.6 mg, hydrogen peroxide urea (Sigma Aldrich) 42 mg, 4 Å molecular sieve (Nacalai Tesque) 20 mg, acetonitrile (Fuji Film Wako Pure Chemical Industries, Ltd.) in a glass tube with an internal volume of 10 mL. Drug) 0.2 mL was added. The mixture was heated to 50 ° C. using an oil bath and stirred, and 50 mg of ethyl ferulate (Tokyo Chemical Industry) dissolved in 0.3 mL was added dropwise to this mixed solution at 0.1 mL every 20 minutes. After 2 hours and 30 minutes, the temperature was returned to room temperature, 3 mL of a 10% aqueous sodium thiosulfate solution (Kishida Chemical) was added to the reaction solution to stop the reaction, and the mixture was stirred for 5 minutes. After adding 10 mL of ethyl acetate (Kishida Chemistry) and performing a liquid separation treatment, the mixture was washed with saturated brine. The ethyl acetate phase was recovered, dried using sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) as a desiccant, and then filtered to concentrate the filtrate to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane to ethyl acetate was changed from 3: 1 to 1: 1), a heterocyclized dimer intermediate was used. The body was obtained at 48.4 mg (46% yield).
（実施例７）＜ファルラ酸の環化二量化前駆体からポアシン酸の合成＞
内容積１０ｍＬのガラス管に実施例４−３により合成したファルラ酸の環化二量化体を３０ｍｇ、０.３５ＮのＮａＯＨ水溶液を３ｍＬ入れ、９０℃で１６時間反応を行なった。その後室温に戻し、１Ｎ塩酸で中和した後、酢酸エチル(キシダ化学)１０ｍＬを加え、分液捜査の後、酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム(富士フィルム 和光純薬製)を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー(関東化学製)を塩化メチレンとメタノール(１００：２)を使用して精製を行った結果、黄色粉末５.４ｍｇ(収率２２％)を得た。その1Ｈ−ＮＭＲ、13Ｃ−ＮＭＲ、ＭＳ分析から、生成物は前記[式１]および[式２]において、Ｒ1とＲ4がＯＭｅで、Ｒ2がＨ、Ｒ3がＯＨであるポアシン酸と同定された。
(Example 7) <Synthesis of poacidic acid from cyclized dimerization precursor of farulic acid>
30 mg of the cyclized dimer of farulic acid synthesized according to Example 4-3 and 3 mL of 0.35 N NaOH aqueous solution were placed in a glass tube having an internal volume of 10 mL, and the reaction was carried out at 90 ° C. for 16 hours. After that, the temperature was returned to room temperature, neutralized with 1N hydrochloric acid, 10 mL of ethyl acetate (Kishida Chemical) was added, and after a liquid separation investigation, the ethyl acetate phase was recovered, and sodium sulfate (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) was added as a desiccant. After the use-drying treatment, the filtrate was concentrated by filtration to obtain an oily substance. As a result of purification of silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using methylene chloride and methanol (100: 2), 5.4 mg (yield 22%) of yellow powder was obtained. From the 1 H-NMR, 13 C-NMR, and MS analysis, the products are R 1 and R 4 in OMe, R 2 in H, and R 3 in OH in the above [Equation 1] and [Equation 2]. It was identified as Poacic acid.
（実施例８）＜クマル酸の環化二量化前駆体からポアシン酸類似体の合成＞
実施例５により合成したクマル酸環化二量化体を、４８.４ｍｇを用いた他は実施例７と同様に操作した。その結果、黄色粉末２０.５ｍｇ(収率５７％)を得た。その1Ｈ−ＮＭＲ、13Ｃ−ＮＭＲ、ＭＳ分析から、生成物は前記[式１]および[式２]において、Ｒ1とＲ4がＨで、Ｒ2がＨ、Ｒ3がＯＨである下記[式８]で表されるポアシン酸類似体と同定された。
The coumaric acid cyclized dimer synthesized in Example 5 was operated in the same manner as in Example 7 except that 48.4 mg was used. As a result, 20.5 mg of yellow powder (yield 57%) was obtained. From the 1 H-NMR, 13 C-NMR, and MS analysis, the products are R 1 and R 4 are H, R 2 is H, and R 3 is OH in the above [Equation 1] and [Equation 2]. It was identified as a Poacidic acid analog represented by the following [Formula 8].
（実施例９）＜ファルラ酸とシナピン酸のヘテロ環化体からポアシン酸類似体の合成＞
実施例６により合成したクファルラ酸とシナピン酸のヘテロ環化体を５０ｍｇを用いた他は実施例７と同様に操作した。その結果、黄色粉末４.５ｍｇ(収率１２％)を得た。その1Ｈ−ＮＭＲ、13Ｃ−ＮＭＲ、ＭＳ分析から、生成物は前記[式１]および[式２]において、Ｒ1とＲ4がＯＭｅで、Ｒ2がＯＭｅ、Ｒ3がＯＨである下記[式９]で表されるポアシン酸類似体と同定された。
The heterocyclic compound of kufarlacic acid and sinapic acid synthesized in Example 6 was operated in the same manner as in Example 7 except that 50 mg was used. As a result, 4.5 mg (yield 12%) of yellow powder was obtained. From the 1 H-NMR, 13 C-NMR, and MS analysis, the products in the above [Equation 1] and [Equation 2] are R 1 and R 4 being OMe, R 2 being OMe, and R 3 being OH. It was identified as a Poacidic acid analog represented by the following [Formula 9].
（実施例１０）＜出芽酵母の増殖阻害試験＞
出芽酵母の実験室株ＢＹ４７４１をＹＰＤ培地(１％ Ｂａｃｔｏ Ｙｅａｓｔ Ｅｘｔｒａｃｔ (BD Biosciences)， ２％ Ｂａｃｏｔｏ Ｐｅｐｔｏｎｅ (BD Biosciences)， ２％ Ｄ−グルコース)で対数増殖期(１×１０7 ｃｅｌｌｓ／ｍＬ)まで培養し、ＹＰＤ培地で５×１０6 ｃｅｌｌｓ／ｍＬに希釈した。次に、９６ｗｅｌｌ ｐｌａｔｅ (Cerning 3598)のｗｅｌｌに８９μＬのＹＰＤと１μＬの１００倍の薬剤ストック(１％ ＤＭＳＯで溶解)を加えた後に、用意した５×１０6 ｃｅｌｌｓ／ｍＬの酵母懸濁液を１０μＬとってｗｅｌｌに加えた。酵母細胞の最終細胞濃度は５×１０6 ｃｅｌｌｓ／ｍＬ、薬剤の最終濃度は０，４，８，１６，３２，６４，１２８，５１２，１０２４μｇ／ｍＬである。２５℃で１８時間震盪培養したのち、吸光マイクロプレートリーダー(Molecular devices, Spectra Max Plus 384)を用いて細胞の増殖度(OD600)を測定した。コントロール条件(１％ ＤＭＳＯ)を１.０として、それぞれの薬剤処理時の増殖程度を示した。その結果を図１に示す。
(Example 10) <Saccharomyces cerevisiae growth inhibition test>
Saccharomyces cerevisiae laboratory strain BY4741 in YPD medium (1% Bacto Yeast Extract (BD Biosciences), 2% Bacoto Peptone (BD Biosciences), 2% D-glucose) up to logarithmic growth phase (1 × 10 7 cells / mL) The cells were cultured and diluted with YPD medium to 5 × 10 6 cells / mL. Next, 89 μL of YPD and 1 μL of 100 times drug stock (dissolved in 1% DMSO) were added to the well of 96 well plate (Cerning 3598), and then the prepared 5 × 10 6 cells / mL yeast suspension was added. 10 μL was taken and added to well. The final cell concentration of yeast cells is 5 × 10 6 cells / mL, and the final drug concentration is 0,4,8,16,32,64,128,512,1024 μg / mL. After shaking culture at 25 ° C. for 18 hours, the degree of cell proliferation (OD600) was measured using an absorption microplate reader (Molecular devices, Spectra Max Plus 384). The degree of proliferation during each drug treatment was shown with the control condition (1% DMSO) set to 1.0. The result is shown in FIG.
図１中、薬剤として、(1)はポアシン酸、(2)は実施例８による[式８]のポアシン酸類似体、(3)は実施例９による[式９]のポアシン酸類似体を添加したものであり、それぞれ抗真菌活性を有することが分かる。それぞれのＩＣ50(５０％阻害濃度)は、(1)が１８０μｇ／ｍＬ、(2)が７５μｇ／ｍＬ、(3)が５００μｇ／ｍＬであり、(2)の[式８]のポアシン酸類似体はポアシン酸より約２倍の抗真菌活性を有することが分かる。 In FIG. 1, as a drug, (1) is a poacic acid analog, (2) is a poacic acid analog according to Example 8 [formula 8], and (3) is a poacic acid analog according to Example 9 [formula 9]. It can be seen that they are added and each has antifungal activity. Each IC 50 (50% inhibitory concentration) is 180 μg / mL for (1), 75 μg / mL for (2), and 500 μg / mL for (3), which are similar to the poacid acid of [Equation 8] of (2). It can be seen that the body has about twice the antifungal activity of poacic acid.
本発明は、フェニル基に少なくとも一つの水酸基もしくはアルコキシ基を持つ桂皮酸誘導体を原料として用い、対応する桂皮酸誘導体二量化物を、安価に収率よく製造するのに有用である。製造した桂皮酸誘導体二量体化合物は、農薬、医薬品、または機能性食品として広く使用されることが期待される。 INDUSTRIAL APPLICABILITY The present invention is useful for producing a corresponding cinnamic acid derivative dimerized at low cost and in high yield by using a cinnamic acid derivative having at least one hydroxyl group or an alkoxy group in the phenyl group as a raw material. The produced cinnamic acid derivative dimer compound is expected to be widely used as a pesticide, a pharmaceutical product, or a functional food.
Claims (14)
An antifungal agent containing the compound of claim 12 or 13 as an active ingredient.
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