JP7369864B2 - Magnolol derivatives, their production methods and uses - Google Patents

Magnolol derivatives, their production methods and uses Download PDF

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JP7369864B2
JP7369864B2 JP2022518375A JP2022518375A JP7369864B2 JP 7369864 B2 JP7369864 B2 JP 7369864B2 JP 2022518375 A JP2022518375 A JP 2022518375A JP 2022518375 A JP2022518375 A JP 2022518375A JP 7369864 B2 JP7369864 B2 JP 7369864B2
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magnolol
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ヂャン，ビン
ジィエン ヂャン，チー
フェイ ウー，ユー
ガン フゥー，ティン
ユン フー，リー
アイ，ヨン
ファン ヂャン，ウェン
チュ，リィエン
ジュブレ，クリステル
ヒロン，フランク
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Guangdong Heji Biotech Co Ltd
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Description

（関連出願の相互参照）
本出願は、２０１９年０９月２０日に出願された中国特許出願２０１９１０８９４２８１．２の権利を主張しており、該出願の内容は引用により本願に組み込まれる。 (Cross reference to related applications)
This application claims rights to Chinese Patent Application No. 201910894281.2 filed on September 20, 2019, the contents of which are incorporated herein by reference.

本発明はマグノロール誘導体の分野に関し、具体的には、マグノロール誘導体、その製造方法及び使用に関する。 The present invention relates to the field of magnolol derivatives, and in particular to magnolol derivatives, their preparation and uses.

食品、医薬品や化粧品は大量の水分と各種の栄養成分を豊富に含んでおり、微生物に良好な生長環境を提供しており、しかも化粧品の生産と使用過程において微生物の侵入は避けられず、このため、化粧品は極めて腐敗や変質しやすく、製品の品質の低下を招き、使用者の健康に脅威をもたらす。化粧品に防腐剤を添加することは、製品を微生物汚染から保護し、製品の貯蔵寿命を延ばし、製品の安全性を確保するための重要な手段である。 Foods, medicines, and cosmetics contain large amounts of water and are rich in various nutritional components, providing a favorable growth environment for microorganisms.Moreover, the invasion of microorganisms during the production and use process of cosmetics is unavoidable. Therefore, cosmetics are extremely susceptible to spoilage and deterioration, leading to a decline in product quality and posing a threat to the health of users. Adding preservatives to cosmetics is an important means to protect products from microbial contamination, extend product shelf life, and ensure product safety.

現在、食品、医薬品や化粧品に使用されている防腐剤の種類は非常に多く、ほとんどは化学防腐剤であり、よく使用されているのは数十種類であり、酸性防腐剤（安息香酸）、エステル型防腐剤（パラベン類）などを含む。しかし、科学の発展と消費者の安全意識の高まりに従って、化学防腐剤の防腐効果はとても良いが、いくつかの化学防腐剤は人体に悪い作用を引き起こし、皮膚のアレルギー、体の機能の低下を引き起こし、そして環境に汚染をもたらすことが相次いで発見された。そのため、天然の防腐剤が各業界において期待されており、低毒性、低刺激、高効率の天然防腐剤は、食品、医薬品や化粧品などの分野で重要な意義がある。 Currently, there are many types of preservatives used in food, medicine, and cosmetics, most of which are chemical preservatives, with dozens of commonly used types including acidic preservatives (benzoic acid), Contains ester-type preservatives (parabens), etc. However, with the development of science and the increasing safety awareness of consumers, although the preservative effect of chemical preservatives is very good, some chemical preservatives may cause bad effects on the human body, causing skin allergies and a decline in body functions. It has been discovered one after another that it causes environmental damage and contaminates the environment. Therefore, natural preservatives are expected in various industries, and natural preservatives with low toxicity, low irritation, and high efficiency are of important significance in fields such as food, medicine, and cosmetics.

厚朴（Ｍａｇｎｏｌｉａ ｏｆｆｉｃｉｎａｌｉｓ ｃｏｒｔｅｘ）はモクレン科植物である厚朴Ｍａｇｎｏｌｉａ ｏｆｆｉｃｉｎａｌｉｓ Ｒｅｈｄ． ｅｔ Ｗｉｌｓ．の乾燥樹皮、根皮及び枝であり、重要な漢方薬であり、『神農本草経』において中品に指定されている。厚朴は、味苦辛、性温であり、行気化湿、温中止痛、降逆平喘の作用がある。厚朴の主要な化学活性成分は、リグナン類、マグノロールやホノキオールなどである。厚朴中のフェノール類には、静菌、抗腫瘍、鎮痛、抗炎症などの効果がある。しかし、水溶性が悪く、酸化変質しやすいため、マグノロールの食品、医薬品や化粧品への使用は制限されている。通常、一般的な界面活性剤、乳化剤を用いてマグノロールを可溶化することができるが、この場合、必要な界面活性剤、乳化剤の使用量が非常に大きいだけでなく、水剤の処方に応用しても、マグノロールは水系の処方から析出し、系全体を白濁させ、使用に深刻な影響を与える。また、処方系に少量のアルカリを加えてマグノロールを塩にすることで水溶性を高めることもできるが、この方法で形成されたマグノロール塩は非常に不安定で黄金色になりやすく、その結果、系の導電率が上昇し、静菌能力が低下する。以上の方法は、製品処方系のｐＨ、増粘剤及び乳化剤の使用量の正確度に対する要求が非常に高いため、工業的応用が困難である。 Magnolia officinalis cortex is a Magnolia officinalis Rehd. et Wils. The dried bark, root bark, and twigs of this plant are important Chinese herbal medicines, and are designated as middle-class products in the Shennong Bencaojing. Goboku has a bitter and spicy taste, and has the effect of calming air and dampness, warming pain, and relieving asthma. The main chemically active components of Hoboku are lignans, magnolol, and honokiol. Phenols in Hokboku have bacteriostatic, antitumor, analgesic, and anti-inflammatory effects. However, because it has poor water solubility and is susceptible to oxidative deterioration, its use in foods, medicines, and cosmetics is limited. Normally, magnolol can be solubilized using common surfactants and emulsifiers, but in this case, not only are the amounts of surfactants and emulsifiers required to be used extremely large, but also Even when applied, magnolol precipitates out of water-based formulations, making the entire system cloudy and seriously affecting its use. It is also possible to increase water solubility by adding a small amount of alkali to the formulation to salt magnolol, but magnolol salts formed in this way are very unstable and tend to turn golden yellow; As a result, the electrical conductivity of the system increases and the bacteriostatic capacity decreases. The above methods are difficult to apply industrially because there are very high requirements for the accuracy of the pH of the product formulation system and the amounts of thickeners and emulsifiers used.

従来、マグノロールの溶解度を高める方法は、元の系に不純化合物を導入し、しかもマグノロールを水剤系に溶解させた後に不安定にさせ、系が変質しやすく、静菌能力が低下する。そのため、マグノロールの構造を改質し、マグノロールの水における溶解度と静菌能力を高めることは、マグノロールを天然防腐剤として食品、医薬品や化粧品に応用する際に早急に解決すべき問題である。 Conventional methods to increase the solubility of magnolol involve introducing impurity compounds into the original system, and making the system unstable after dissolving magnolol into the aqueous system, resulting in easy deterioration of the system and a decrease in bacteriostatic ability. . Therefore, modifying the structure of magnolol and increasing its water solubility and bacteriostatic ability are urgent issues that need to be solved when applying magnolol as a natural preservative in food, medicine, and cosmetics. be.

本発明の目的は、マグノロールの水溶性が悪く、水剤系に溶解した後静菌能力が低下するという問題を解決するために、マグノロール誘導体、その製造方法及び使用を提供することである。本発明で提供される水溶性マグノロール誘導体は、防腐剤に適用されると、優れた安定性及び静菌能力を有する。 An object of the present invention is to provide a magnolol derivative, a method for producing it, and its use in order to solve the problem that magnolol has poor water solubility and its bacteriostatic ability decreases after being dissolved in an aqueous drug system. . The water-soluble magnolol derivative provided in the present invention has excellent stability and bacteriostatic ability when applied as a preservative.

上述目的を実現するために、第１の態様において、本発明は、式（１）で表される構造を有するマグノロール誘導体を提供する。 In order to achieve the above object, in a first aspect, the present invention provides a magnolol derivative having a structure represented by formula (1).

Figure 0007369864000001
Figure 0007369864000001

式（１）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素、ハロゲン、置換又は非置換のＣ1～Ｃ10のアルキル、置換又は非置換のＣ1～Ｃ12のアルコキシ、置換又は非置換のＣ6～Ｃ10のアリールから選択される１種であり、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ハロゲン、Ｃ1～Ｃ6のアルコキシ又はＣ6～Ｃ10のアリールから選択される。 In formula (1), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 to C 10 aryl, and the substituents that may be present on R 1 , R 2 , R 3 and R 4 are each independently is selected from halogen, C 1 -C 6 alkoxy or C 6 -C 10 aryl.

好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、置換又は非置換のＣ1～Ｃ10のアルキルであり、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ヒドロキシ、カルボキシ、Ｃ1～Ｃ6のアルコキシ又は一般式が－Ｏ－Ｒ9－ＯＨ構造である基から選択され、ここで、Ｒ9はＣ1～Ｃ6のアルキレンである。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently substituted or unsubstituted C 1 -C 10 alkyl, and R 1 , R 2 , R 3 and R 4 are present on R 1 , R 2 , R 3 and R 4 . The optional substituents are each independently selected from hydroxy, carboxy, C 1 -C 6 alkoxy or groups whose general formula is the structure -O-R 9 -OH, where R 9 is C 1 to C 6 alkylene.

好ましくは、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素、Ｃ6～Ｃ10のアリール又はＣ1～Ｃ6のアルキルから選択される。 Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 to C 10 aryl or C 1 to C 6 alkyl.

第２の態様において、本発明は、マンニッヒ反応条件下で、式（２）及び／又は式（４）の構造を有する化合物と式（３）及び／又は式（５）の構造を有する化合物との第１接触を行い、その後、第１の接触により得られる生成物と式（６）の構造を有する化合物との第２接触を行い、マンニッヒ反応生成物を得ることを含む、マグノロール誘導体の製造方法を提供する。 In a second aspect, the present invention provides a compound having a structure of formula (2) and/or formula (4) and a compound having a structure of formula (3) and/or formula (5) under Mannich reaction conditions. and then a second contact of the product obtained by the first contact with a compound having the structure of formula (6) to obtain a Mannich reaction product. A manufacturing method is provided.

Figure 0007369864000002
Figure 0007369864000002

式（２）及び式（４）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、置換又は非置換のＣ1～Ｃ10のアルキルであり、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ヒドロキシ、カルボキシ、Ｃ1～Ｃ6のアルコキシ又は一般式が－Ｏ－Ｒ9－ＯＨ構造である基から選択され、ここで、Ｒ9はＣ1～Ｃ6のアルキレンである。 In formula (2) and formula (4), R 1 , R 2 , R 3 and R 4 are each independently substituted or unsubstituted C 1 to C 10 alkyl, and R 1 , R 2 , The substituents that may be present on R 3 and R 4 are each independently selected from hydroxy, carboxy, C 1 -C 6 alkoxy or groups whose general formula is -O-R 9 -OH structure. , where R 9 is C 1 -C 6 alkylene.

好ましくは、式（３）及び式（５）中、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素、Ｃ6～Ｃ10のアリール又はＣ1～Ｃ6のアルキルから選択される。 Preferably, in formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 each independently represent hydrogen, C 6 -C 10 aryl or C 1 -C 6 alkyl. selected.

好ましくは、式（６）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素、ハロゲン、置換又は非置換のＣ1～Ｃ10のアルキル、置換又は非置換のＣ1～Ｃ12のアルコキシ、置換又は非置換のＣ6～Ｃ10のアリールから選択される１種であり、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ハロゲン、Ｃ1～Ｃ6のアルコキシ又はＣ6～Ｃ10のアリールから選択される。 Preferably, in formula (6), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 10 alkyl, substituted or unsubstituted C One type selected from 1 to C 12 alkoxy, substituted or unsubstituted C 6 to C 10 aryl, and the substituents that may be present on R 1 , R 2 , R 3 and R 4 are: Each independently selected from halogen, C 1 -C 6 alkoxy or C 6 -C 10 aryl.

第３の態様において、本発明は、前記第１の態様として記載のマグノロール誘導体及び前記第２の態様として記載の前記方法で製造されたマグノロール誘導体の静菌における使用を提供する。 In a third aspect, the invention provides a bacteriostatic use of a magnolol derivative as described in the first aspect and a magnolol derivative produced by the method as described in the second aspect.

本発明では、マグノロール構造を変性することで、静菌可能な変性マグノロール誘導体を製造し、このマグノロール誘導体は、良好な水溶性を有し、溶解後無色で透明であり、従来のグラム陰性菌、グラム陽性菌、真菌などに対して顕著な阻害効果を有し、自然に優しい天然防腐剤として食品、医薬品や化粧品などの分野に適用できる。 In the present invention, a bacteriostatic modified magnolol derivative is produced by modifying the magnolol structure. It has a remarkable inhibitory effect on negative bacteria, Gram-positive bacteria, fungi, etc., and can be applied as a nature-friendly natural preservative in fields such as food, medicine, and cosmetics.

本発明の他の特徴及び利点は、後記の発明を実施するための形態の部分において詳細に説明する。 Other features and advantages of the invention are described in detail in the detailed description section below.

実施例１で製造されるマグノロール誘導体の飛行質量スペクトルである。1 is a flight mass spectrum of the magnolol derivative produced in Example 1. 実施例１で製造されるマグノロール誘導体の液体質量正イオン化図である。2 is a liquid mass positive ionization diagram of a magnolol derivative produced in Example 1. FIG. 実施例１で製造されるマグノロール誘導体の液体質量負イオン化図である。1 is a liquid mass negative ionization diagram of a magnolol derivative produced in Example 1. FIG. 実施例３で製造されるマグノロール誘導体の飛行質量スペクトルである。3 is a flight mass spectrum of the magnolol derivative produced in Example 3. 実施例３で製造されるマグノロール誘導体の液体質量正イオン化図である。FIG. 3 is a liquid mass positive ionization diagram of a magnolol derivative produced in Example 3. 実施例３で製造されるマグノロール誘導体の液体質量負イオン化図である。3 is a liquid mass negative ionization diagram of a magnolol derivative produced in Example 3. FIG. 実施例３で製造されるマグノロール誘導体の核磁気スペクトルである。3 is a nuclear magnetic spectrum of the magnolol derivative produced in Example 3.

以下、本発明の具体的な実施形態について詳細に説明する。なお、本明細書に説明される具体的な実施形態は、本発明を説明、解釈するためにのみ使用され、本発明を限定するものではない。 Hereinafter, specific embodiments of the present invention will be described in detail. Note that the specific embodiments described in this specification are used only to explain and interpret the present invention, and are not intended to limit the present invention.

本明細書で開示される範囲の端点及びいかなる値も、この正確な範囲又は値に限定されるものではなく、これらの範囲又は値は、これらの範囲又は値に近い値を含むものとして理解されるべきである。数値範囲の場合、様々な範囲の端点値間、様々な範囲の端点値と個々の点値間、及び個々の点値間は互いに組み合わせられて１つ又は複数の新しい数値の範囲を構成することができ、これらの数値の範囲は、本明細書において具体的に開示されるものとみなされるべきである。 Endpoints of ranges and any values disclosed herein are not intended to be limited to this precise range or value, but are to be understood as including values near those ranges or values. Should. In the case of numerical ranges, between the endpoint values of the various ranges, between the endpoint values of the various ranges and individual point values, and between the individual point values may be combined with each other to constitute one or more new numerical ranges. and these numerical ranges should be considered as specifically disclosed herein.

以下、本発明に関連する用語の一部を説明する。 Some of the terms related to the present invention will be explained below.

「Ｃ1～Ｃ10のアルキル」は炭素数１～１０のアルキルを表し、直鎖アルキル、分岐アルキル又は環状アルキルを含み、具体的には、炭素数１、２、３、４、５、６、７、８、９、１０の直鎖アルキル、分岐アルキルもしくは環状アルキルであってもよく、例えばメチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ｎ－ヘキシル、ｎ－ヘプチル、ｎ－オクチル、ｎ－ノニル、ｎ－デシル、シクロプロピル、メチルシクロプロピル、エチルシクロプロピル、シクロペンチル、メチルシクロペンチル、シクロヘキシルなどであってもよい。 “C 1 to C 10 alkyl” represents an alkyl having 1 to 10 carbon atoms, and includes straight chain alkyl, branched alkyl, and cyclic alkyl, and specifically includes 1, 2, 3, 4, 5, and 6 carbon atoms. , 7, 8, 9, 10 linear alkyl, branched alkyl or cyclic alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl. , n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, and the like.

「Ｃ1～Ｃ12のアルコキシ」は炭素数１～１２のアルコキシを示し、直鎖アルコキシ、分岐アルコキシ及び環状アルコキシを含み、具体的には、炭素数１、２、３、４、５、６、７、８、９、１０、１１、１２の直鎖アルコキシ、分岐アルコキシ又は環状アルコキシであってもよく、例えばメトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペントキシ、イソペンチルオキシ、ｎ－ヘキシルオキシ、ｎ－ヘプチルオキシ、ｎ－オクチルオキシ、ｎ－ノニルオキシ、ｎ－デシルオキシ、シクロプロポキシ、メチルシクロプロポキシ、エチルシクロプロポキシ、シクロペンチルオキシ、メチルシクロペンチルオキシ、シクロヘキシルオキシなどであってもよい。 “C 1 to C 12 alkoxy” refers to alkoxy having 1 to 12 carbon atoms, and includes straight chain alkoxy, branched alkoxy, and cyclic alkoxy, and specifically includes 1, 2, 3, 4, 5, and 6 carbon atoms. , 7, 8, 9, 10, 11, 12 linear alkoxy, branched alkoxy or cyclic alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, cyclopropoxy, methylcyclopropoxy, ethylcyclopropoxy, cyclopentyloxy, methylcyclopentyloxy, cyclohexyl It may also be oxy or the like.

「Ｃ6～Ｃ10のアリール」は炭素数６～１０のアリールを示し、該アリールのベンゼン環上の少なくとも１つのＨはＣ1～Ｃ4のアルキルで置換され、例えばメチルフェニル、エチルフェニル、ｎ－プロピルフェニル、イソプロピルフェニル、ｎ－ブチルフェニル、ｏ－キシリル、ｍ－キシリル、ｐ－キシリルなどが挙げられる。 "C 6 to C 10 aryl" refers to an aryl having 6 to 10 carbon atoms, and at least one H on the benzene ring of the aryl is substituted with a C 1 to C 4 alkyl, such as methylphenyl, ethylphenyl, Examples include n-propylphenyl, isopropylphenyl, n-butylphenyl, o-xylyl, m-xylyl, p-xylyl, and the like.

本明細書の他の同様の基の定義は、本明細書の前述定義を参照しており、炭素原子の数と異性化方式のみが異なる。 Other similar radical definitions herein refer to the previous definitions herein and differ only in the number of carbon atoms and the mode of isomerization.

第１の態様において、本発明は、式（１）で表される構造を有するマグノロール誘導体を提供する。 In a first aspect, the present invention provides a magnolol derivative having a structure represented by formula (1).

Figure 0007369864000003
Figure 0007369864000003

式（１）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素、ハロゲン、置換又は非置換のＣ1～Ｃ10のアルキル、置換又は非置換のＣ1～Ｃ12のアルコキシ、置換又は非置換のＣ6～Ｃ10のアリールから選択される１種であり、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ハロゲン、Ｃ1～Ｃ6のアルコキシ又はＣ6～Ｃ10のアリールから選択される。好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、置換又は非置換のＣ1～Ｃ10のアルキルである。
好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ヒドロキシ、カルボキシ、Ｃ1～Ｃ6のアルコキシ又は一般式が－Ｏ－Ｒ9－ＯＨ構造である基から選択される。ここで、Ｒ9はＣ1～Ｃ6のアルキレンである。
好ましくは、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素、Ｃ6～Ｃ10のアリール又はＣ1～Ｃ6のアルキルから選択される。 In formula (1), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 12 alkoxy, substituted or unsubstituted C 6 to C 10 aryl, and the substituents that may be present on R 1 , R 2 , R 3 and R 4 are each independently is selected from halogen, C 1 -C 6 alkoxy or C 6 -C 10 aryl. Preferably, R 1 , R 2 , R 3 and R 4 are each independently substituted or unsubstituted C 1 -C 10 alkyl.
Preferably, the substituents that may be present on R 1 , R 2 , R 3 and R 4 are each independently hydroxy, carboxy, C 1 -C 6 alkoxy or having the general formula -O-R 9 selected from groups having the structure -OH. Here, R 9 is C 1 -C 6 alkylene.
Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 to C 10 aryl or C 1 to C 6 alkyl.

本発明の１つの好ましい実施形態によれば、式（１）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素、フッ素、塩素、臭素、置換又は非置換のＣ1～Ｃ5のアルキル、置換又は非置換のＣ1～Ｃ6のアルコキシ、置換又は非置換のＣ6～Ｃ8のアリールから選択される１種である。Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、フッ素、塩素、臭素、Ｃ1～Ｃ3のアルコキシ又はＣ6～Ｃ8のアリールから選択される。 According to one preferred embodiment of the invention, in formula (1), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, fluorine, chlorine, bromine, substituted or unsubstituted C It is one selected from 1 to C5 alkyl, substituted or unsubstituted C1 to C6 alkoxy, and substituted or unsubstituted C6 to C8 aryl. The optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from fluorine, chlorine, bromine, C 1 -C 3 alkoxy or C 6 -C 8 aryl be done.

好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、置換又は非置換のＣ1～Ｃ5のアルキルである。Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ヒドロキシ、カルボキシ、Ｃ1～Ｃ3のアルコキシ又は一般式が－Ｏ－Ｒ9－ＯＨ構造である基から選択される。ここで、Ｒ9はＣ1～Ｃ3のアルキレンである。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently substituted or unsubstituted C 1 -C 5 alkyl. The substituents that may be present on R 1 , R 2 , R 3 and R 4 are each independently hydroxy, carboxy, C 1 -C 3 alkoxy, or a group whose general formula is -O-R 9 -OH structure. selected from the group. Here, R 9 is C 1 -C 3 alkylene.

好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素である。
好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、メチル、

Figure 0007369864000004

である。 Preferably, R 1 , R 2 , R 3 and R 4 are each independently hydrogen.
Preferably, R 1 , R 2 , R 3 and R 4 are each independently methyl,
Figure 0007369864000004
It is.

好ましくは、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素、Ｃ6～Ｃ8のアリール又はＣ1～Ｃ3のアルキルから選択される。ここで、Ｃ6～Ｃ8のアリールは、例えばフェニル、メチルフェニル、ｏ－ジメチルフェニル、ｍ－ジメチルフェニル、ｐ－ジメチルフェニル、エチルフェニルのうちの１種であってもよい。 Preferably, R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 6 -C 8 aryl or C 1 -C 3 alkyl. Here, the C 6 -C 8 aryl may be, for example, one of phenyl, methylphenyl, o-dimethylphenyl, m-dimethylphenyl, p-dimethylphenyl, ethylphenyl.

Ｃ1～Ｃ3のアルキルとして、例えばメチル、エチル、ｎ－プロピル又はイソプロピルであってもよい。 C 1 -C 3 alkyl can be, for example, methyl, ethyl, n-propyl or isopropyl.

本発明によれば、好ましくは、式（１）中、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である。 According to the invention, preferably in formula (1) R 5 , R 6 , R 7 and R 8 are all hydrogen.

本発明の１つの好ましい実施形態によれば、式（１）で表される構造を有するマグノロール誘導体は、以下の化合物から選択される少なくとも１種である。 According to one preferred embodiment of the present invention, the magnolol derivative having the structure represented by formula (1) is at least one selected from the following compounds.

Figure 0007369864000005
Figure 0007369864000005

Figure 0007369864000006
Figure 0007369864000006

Figure 0007369864000007
Figure 0007369864000007

Figure 0007369864000008
Figure 0007369864000008

Figure 0007369864000009
Figure 0007369864000009

本発明の発明者は、この好ましい実施形態にかかるマグノロール誘導体がより優れた水溶性及び静菌能力を有することを発見した。 The inventors of the present invention have discovered that the magnolol derivative according to this preferred embodiment has better water solubility and bacteriostatic ability.

第２の態様において、本発明は、マンニッヒ反応条件下で、式（２）及び／又は式（４）の構造を有する化合物と式（３）及び／又は式（５）の構造を有する化合物との第１接触を行い、その後、第１の接触により得られる生成物と式（６）の構造を有する化合物との第２接触を行い、マンニッヒ反応生成物を得ることを含むマグノロール誘導体の製造方法を提供する。 In a second aspect, the present invention provides a compound having a structure of formula (2) and/or formula (4) and a compound having a structure of formula (3) and/or formula (5) under Mannich reaction conditions. and then a second contact of the product obtained by the first contact with a compound having the structure of formula (6) to obtain a Mannich reaction product. provide a method.

Figure 0007369864000010
Figure 0007369864000010

式（２）及び式（４）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、置換又は非置換のＣ1～Ｃ10のアルキルである。
好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ヒドロキシ、カルボキシ、Ｃ1～Ｃ6のアルコキシ又は一般式が－Ｏ－Ｒ9－ＯＨ構造である基から選択される。ここで、Ｒ9はＣ1～Ｃ6のアルキレンである。
好ましくは、式（３）及び式（５）中、Ｒ5、Ｒ6、Ｒ7及びＲ8は、それぞれ独立して、水素、Ｃ6～Ｃ10のアリール又はＣ1～Ｃ6のアルキルから選択される。
好ましくは、式（６）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、それぞれ独立して、水素、ハロゲン、置換又は非置換のＣ1～Ｃ10のアルキル、置換又は非置換のＣ1～Ｃ12のアルコキシ、置換又は非置換のＣ6～Ｃ10のアリールから選択される１種である。
好ましくは、Ｒ1、Ｒ2、Ｒ3及びＲ4上に存在してもよい置換基は、それぞれ独立して、ハロゲン、Ｃ1～Ｃ6のアルコキシ又はＣ6～Ｃ10のアリールから選択される。 In formulas (2) and (4), R 1 , R 2 , R 3 and R 4 are each independently substituted or unsubstituted C 1 to C 10 alkyl.
Preferably, the substituents that may be present on R 1 , R 2 , R 3 and R 4 are each independently hydroxy, carboxy, C 1 -C 6 alkoxy or having the general formula -O-R 9 selected from groups having the structure -OH. Here, R 9 is C 1 -C 6 alkylene.
Preferably, in formula (3) and formula (5), R 5 , R 6 , R 7 and R 8 each independently represent hydrogen, C 6 -C 10 aryl or C 1 -C 6 alkyl. selected.
Preferably, in formula (6), R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 10 alkyl, substituted or unsubstituted C It is one selected from 1 to C 12 alkoxy and substituted or unsubstituted C 6 to C 10 aryl.
Preferably, the optional substituents on R 1 , R 2 , R 3 and R 4 are each independently selected from halogen, C 1 -C 6 alkoxy or C 6 -C 10 aryl. Ru.

上記の式（２）～式（６）中、前記Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びＲ8の可能な範囲は、前述の第１の態様におけるＲ1、Ｒ2、Ｒ3、Ｒ4、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びＲ8の可能な範囲と同じであり、ここでは詳しく説明しない。 In the above formulas (2) to (6), R 1 , R 2 , R 3 , R 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The possible range is the possible range of R 1 , R 2 , R 3 , R 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 in the first embodiment. This is the same as the range and will not be explained in detail here.

本発明によれば、前記式（２）及び／又は式（４）の構造を有する化合物は、アミン系化合物である。本発明では、前記アミン系化合物の場合、使用可能な範囲が広く、直鎖アルキルアミン、分岐アルキルアミン、シクロアルキルアミン、ヒドロキシアルキルアミン又は各種アミノ酸であってもよく、好ましくは二級アミンである。本発明では、前記二級アミンについて特に限定がなく、好ましくは、Ｎ－メチル－グリシン、Ｎ－エチル－グリシン、Ｎ－メチル－アミノエトキシエタノール、Ｎ－エチル－アミノエトキシエタノール、メチルアミノアセトアルデヒドジメチルアセタール、メチルアミノアセトアルデヒドジエチルアセタール、エチルアミノアセトアルデヒドジメチルアセタール、ジエタノールアミン、ジメチルアミン、ジエチルアミン及びジ－ｎ－プロピルアミンのうちの少なくとも１種であり、さらに好ましくは、ジエタノールアミン、ジメチルアミン、ジエチルアミン、及びジ－ｎ－プロピルアミンのうちの少なくとも１種である。本発明の好ましい態様を採用することにより、製造されたマグノロール誘導体の静菌性能及び製品収率をより向上させる点で有利である。 According to the present invention, the compound having the structure of formula (2) and/or formula (4) is an amine compound. In the present invention, the amine compound can be used in a wide range, and may be a linear alkylamine, a branched alkylamine, a cycloalkylamine, a hydroxyalkylamine, or various amino acids, and is preferably a secondary amine. . In the present invention, the secondary amine is not particularly limited, and is preferably N-methyl-glycine, N-ethyl-glycine, N-methyl-aminoethoxyethanol, N-ethyl-aminoethoxyethanol, or methylaminoacetaldehyde dimethyl acetal. , methylaminoacetaldehyde diethylacetal, ethylaminoacetaldehyde dimethylacetal, diethanolamine, dimethylamine, diethylamine, and di-n-propylamine, more preferably diethanolamine, dimethylamine, diethylamine, and di-n-propylamine. - at least one propylamine. Adopting the preferred embodiments of the present invention is advantageous in that the bacteriostatic performance and product yield of the produced magnolol derivative can be further improved.

本発明によれば、前記式（３）及び／又は式（５）の構造を有する化合物は、アルデヒド系化合物である。本発明では、前記アルデヒド系化合物の場合、使用可能な範囲が広く、好ましくは、使用されるアルデヒド系化合物は、ホルムアルデヒド、アセトアルデヒド、プロピオンアルデヒド、ベンズアルデヒド、フェニルアセトアルデヒド及びｏ－メチルベンズアルデヒドのうちの少なくとも１種であってもよく、より好ましくはホルムアルデヒドである。本発明の好ましい態様を採用することにより、製造されたマグノロール誘導体の静菌性能をより向上させる点で有利である。 According to the present invention, the compound having the structure of formula (3) and/or formula (5) is an aldehyde compound. In the present invention, the aldehyde compound can be used in a wide range, and preferably, the aldehyde compound used is at least one of formaldehyde, acetaldehyde, propionaldehyde, benzaldehyde, phenylacetaldehyde, and o-methylbenzaldehyde. It may be a seed, more preferably formaldehyde. Adopting the preferred embodiments of the present invention is advantageous in that the bacteriostatic performance of the produced magnolol derivative can be further improved.

式（２）及び／又は式（４）の構造を有する化合物、式（３）及び／又は式（５）の構造を有する化合物及び式（６）の構造を有する化合物により製造されたマグノロール誘導体の静菌性能の調節作用を十分に発揮させるために、好ましくは、式（２）及び／又は式（４）の構造を有する化合物の総量と、式（３）及び／又は式（５）の構造を有する化合物の総量と、式（６）の構造を有する化合物とのモル比は、０．５～６：０．５～６：１、より好ましくは、１～４：１～４：１である。 Magnolol derivatives produced from compounds having the structure of formula (2) and/or formula (4), compounds having the structure of formula (3) and/or formula (5), and compounds having the structure of formula (6) In order to fully exhibit the effect of regulating the bacteriostatic performance of the compound, preferably, the total amount of the compound having the structure of formula (2) and/or formula (4), and the total amount of the compound having the structure of formula (3) and/or formula (5) The molar ratio between the total amount of compounds having the structure and the compound having the structure of formula (6) is 0.5 to 6:0.5 to 6:1, more preferably 1 to 4:1 to 4:1. It is.

本発明の１つの好ましい実施形態によれば、前記第１接触及び第２接触は、すべて酸性物質及び溶媒の存在下で行われる。本発明では、前記酸性物質は触媒として機能する。 According to one preferred embodiment of the invention, the first contact and the second contact are all carried out in the presence of an acidic substance and a solvent. In the present invention, the acidic substance functions as a catalyst.

本発明によれば、好ましくは、前記酸性物質は、塩酸、リン酸、硫酸、及び酢酸から選択される少なくとも１種である。本発明は、前記塩酸、リン酸、硫酸又は酢酸の濃度について制限がなく、当業者は実際の需要に応じて自由に選択することができる。 According to the present invention, preferably the acidic substance is at least one selected from hydrochloric acid, phosphoric acid, sulfuric acid, and acetic acid. In the present invention, the concentration of hydrochloric acid, phosphoric acid, sulfuric acid, or acetic acid is not limited, and those skilled in the art can freely select it according to actual needs.

本発明によれば、好ましくは、前記溶媒は、水及び／又は有機溶媒である。 According to the invention, preferably said solvent is water and/or an organic solvent.

本発明では、前記有機溶媒は特に限定されておらず、本分野における任意の有機溶媒であってもよく、好ましくは極性有機溶媒であり、さらに好ましくはヒドロキシ又はカルボニルを含有する極性溶媒であり、より好ましくは、前記有機溶媒は、メタノール、エタノール、イソプロパノール及び酢酸から選択される少なくとも１種であり、さらに好ましくは、メタノール及び／又はエタノールである。本発明では、前記有機溶媒及び酸性物質の両方が酢酸である場合、酢酸の使用量は、触媒に必要な酸性物質を満たすことができる使用量であればよく、該使用量でマグノロールを溶解できない場合、他の溶媒（例えば、メタノール及び／又はエタノール）と組み合わせて使用することができ、本発明はこれについて限定しない。 In the present invention, the organic solvent is not particularly limited, and may be any organic solvent in this field, preferably a polar organic solvent, more preferably a polar solvent containing hydroxy or carbonyl, More preferably, the organic solvent is at least one selected from methanol, ethanol, isopropanol, and acetic acid, and still more preferably methanol and/or ethanol. In the present invention, when both the organic solvent and the acidic substance are acetic acid, the amount of acetic acid used may be any amount that can satisfy the acidic substance required for the catalyst, and the amount used can dissolve magnolol. If not, it can be used in combination with other solvents (eg methanol and/or ethanol), and the invention is not limited thereto.

本発明は、前記マンニッヒ反応の進行に有利である限り、前記酸性物質及び溶媒の使用量について制限はなく、好ましくは、前記式（２）及び／又は式（４）の構造を有する化合物、式（３）及び／又は式（５）の構造を有する化合物、及び式（６）の構造を有する化合物の総量に対して、前記酸性物質の使用量は０．０３～１０ｍＬ／ｇであり、前記溶媒の使用量は２～１５ｍＬ／ｇである。例えば、前記式（２）及び／又は式（４）の構造を有する化合物、式（３）及び／又は式（５）の構造を有する化合物、及び式（６）の構造を有する化合物の総量を１ｇとした場合、前記酸性物質の使用量は０．０３～１０ｍＬであり、前記溶媒の使用量は２～１５ｍＬである。本発明では、ここで酸性物質及び溶媒の使用量は、第１接触における対応する使用量と第２接触における対応する使用量との合計を意味する。本発明は、前記第１接触における酸性物質及び溶媒のそれぞれの使用量と、第２接触におけるそれぞれの使用量との比を限定するものではなく、当業者が必要に応じて自由に選択することができ、例えば、前記第１接触における酸性物質及び溶媒の総使用量と第２接触における対応する総使用量との体積比は１：０．５～０．８である。 In the present invention, there is no restriction on the amount of the acidic substance and solvent used as long as it is advantageous for the progress of the Mannich reaction, and preferably compounds having the structure of the formula (2) and/or formula (4), the formula The amount of the acidic substance used is 0.03 to 10 mL/g based on the total amount of the compound having the structure of (3) and/or formula (5) and the compound having the structure of formula (6), and the amount of the acidic substance used is 0.03 to 10 mL/g, The amount of solvent used is 2-15 mL/g. For example, the total amount of the compound having the structure of formula (2) and/or formula (4), the compound having the structure of formula (3) and/or formula (5), and the compound having the structure of formula (6), In the case of 1 g, the amount of the acidic substance used is 0.03 to 10 mL, and the amount of the solvent used is 2 to 15 mL. In the present invention, the amount of acidic substance and solvent used herein means the sum of the corresponding amounts used in the first contact and the corresponding amounts used in the second contact. The present invention does not limit the ratio of the amounts of the acidic substance and solvent used in the first contact to the amounts used in the second contact, and those skilled in the art can freely select them as necessary. For example, the volume ratio of the total amount of the acidic substance and solvent used in the first contact to the corresponding total amount used in the second contact is 1:0.5 to 0.8.

本発明の１つの好ましい実施形態によれば、前記マグノロール誘導体の製造方法は、マンニッヒ反応条件、並びに酸性物質及び溶媒の存在下で、式（２）及び／又は式（４）の構造を有する化合物と式（３）及び／又は式（５）の構造を有する化合物とを混合して第１接触を行い、その後、第１接触により得られる生成物と式（６）の構造を有する化合物との第２接触を行うことを含む。本発明は、前記酸性物質の添加タイミングを特に限定するものではなく、例えば、酸性物質を第１接触又は第２接触の反応物に直接添加してもよいし、前記酸性物質を溶媒に添加して混合した後、前記第１接触又は第２接触の反応物、好ましくは後者に一緒に添加してもよい。本発明における前記混合は、いずれも撹拌下で行うことが好ましい。 According to one preferred embodiment of the present invention, the method for producing the magnolol derivative has a structure of formula (2) and/or formula (4) under Mannich reaction conditions and in the presence of an acidic substance and a solvent. A first contact is performed by mixing the compound and a compound having the structure of formula (3) and/or formula (5), and then a product obtained by the first contact and a compound having the structure of formula (6) are mixed. including making a second contact. The present invention does not particularly limit the timing of addition of the acidic substance; for example, the acidic substance may be added directly to the reactant of the first contact or the second contact, or the acidic substance may be added to the solvent. After mixing, it may be added to the reactants of the first or second contact, preferably the latter. It is preferable that the above-mentioned mixing in the present invention is performed under stirring.

好ましくは、前記第１接触の方式は以下を含む。まず、式（３）及び／又は式（５）の構造を有する化合物（アルデヒド系化合物又はその溶液が好ましく、この溶液は水溶液であることが好ましい）を、式（２）及び／又は式（４）の構造を有する化合物（好ましくは二級アミン化合物又はその溶液が好ましく、この溶液は水溶液であることが好ましい）に加えて接触させ、温度を２０～５０℃、好ましくは３０～４０℃、時間を５～２０ｍｉｎ、好ましくは１０～１５ｍｉｎに制御し、次に、第１接触の系を低温水浴に置き、酸性物質又は酸性物質の溶媒（好ましくは有機溶媒）における溶液を前記系に加え、温度を１～１０℃、好ましくは２～５℃、さらなる接触の時間を０．５～２ｈ、好ましくは０．６～１．５ｈに制御する。本発明は、低温水浴の目的が達成される限り、前記低温水浴の形態を特に限定せず、好ましくは、氷水浴及び／又は氷塩浴であり、本発明は、前記氷塩浴中の塩を特に限定せず、好ましくは、塩化カリウム、塩化ナトリウム、硫酸ナトリウム、硫酸カリウムのうちの少なくとも１種である。前記氷塩浴中の塩の使用量は、水の重量に対して０．５～５重量％である。 Preferably, the first contact method includes the following. First, a compound having the structure of formula (3) and/or formula (5) (preferably an aldehyde compound or a solution thereof, and this solution is preferably an aqueous solution) is added to the compound having the structure of formula (2) and/or formula (5). ) (preferably a secondary amine compound or a solution thereof; this solution is preferably an aqueous solution) and brought into contact at a temperature of 20 to 50°C, preferably 30 to 40°C, for a period of time. is controlled at 5-20 min, preferably 10-15 min, then the system of the first contact is placed in a low temperature water bath, the acidic substance or a solution of the acidic substance in a solvent (preferably an organic solvent) is added to said system, and the temperature is controlled at 1-10° C., preferably 2-5° C., and the time of further contact is controlled at 0.5-2 h, preferably 0.6-1.5 h. The present invention does not particularly limit the form of the low-temperature water bath as long as the purpose of the low-temperature water bath is achieved, and preferably it is an ice-water bath and/or an ice-salt bath. is not particularly limited, and is preferably at least one of potassium chloride, sodium chloride, sodium sulfate, and potassium sulfate. The amount of salt used in the ice salt bath is 0.5 to 5% by weight based on the weight of water.

好ましくは、前記第２接触の方式は、酸性物質の存在下で、式（６）の構造を有する化合物を前記溶媒に溶解して溶液を形成し、その後、３０～９０℃で第１接触により得られる生成物と第２接触を行うことを含む。 Preferably, in the second contacting method, the compound having the structure of formula (6) is dissolved in the solvent in the presence of an acidic substance to form a solution, and then the first contacting is performed at 30 to 90°C. making a second contact with the resulting product.

本発明者らは、上記のように前記酸性物質を溶媒に加えて混合した後、前記第１接触又は第２接触の反応物に一緒に加える好ましい方式は、反応物に酸を直接加える方法と比較して、酸ミストを効果的に低減し、反応発熱が激しく副反応を生じることを回避できることを見出した。 The present inventors believe that a preferred method of adding the acidic substance to the solvent and mixing it together with the reactants of the first contact or second contact is a method of directly adding the acid to the reactants. In comparison, it has been found that acid mist can be effectively reduced and side reactions caused by severe exothermic reaction can be avoided.

本発明によれば、好ましくは、前記マンニッヒ反応条件には、第１接触の温度が１～５０℃、より好ましくは２～５０℃であることと、第２接触の温度が３０～９０℃、より好ましくは７０～８５℃であることとが含まれる。 According to the present invention, preferably, the Mannich reaction conditions include the temperature of the first contact being 1 to 50°C, more preferably 2 to 50°C, and the temperature of the second contact being 30 to 90°C, More preferably, the temperature is 70 to 85°C.

好ましくは、前記マンニッヒ反応条件には、第１接触の時間が５ｍｉｎ～２ｈ、より好ましくは１０ｍｉｎ～２ｈであることと、第２接触の時間が１～２０ｈ、より好ましくは５～１０ｈであることとがさらに含まれる。本発明では、前記第１接触の時間は、第１接触の合計時間を意味し、前記第２接触の時間は、第２接触の合計時間を意味する。 Preferably, the Mannich reaction conditions include a first contact time of 5 min to 2 h, more preferably 10 min to 2 h, and a second contact time of 1 to 20 h, more preferably 5 to 10 h. It further includes. In the present invention, the time of the first contact means the total time of the first contact, and the time of the second contact means the total time of the second contact.

本発明の１つの好ましい実施形態によれば、該方法は、第２接触の生成物を順次に蒸発、精製、及び凍結乾燥することをさらに含む。本発明は、前記蒸発操作を特に限定するものではなく、本技術分野の蒸発装置のいずれであってもよく、好ましくは、ロータリーエバポレータを用いて有機溶媒の大部分を蒸発除去する。本発明は、前記精製操作を特に限定するものではなく、当該分野における精製方法のいずれかであってもよく、好ましくはカラムクロマトグラフィーの方法を使用し、精製充填剤は１００～２００メッシュのシリカゲルであり、本発明はカラムクロマトグラフィーで使用される溶出剤を特に限定せず、溶出目的を達成する当該分野における任意の試薬であってもよく、好ましくは、溶出剤は酢酸エチル／アセトンであり、前記酢酸エチルとアセトンとの体積比が好ましくは２～６：１、特に好ましくは４：１である。 According to one preferred embodiment of the invention, the method further comprises sequentially evaporating, purifying and lyophilizing the product of the second contact. The present invention does not particularly limit the evaporation operation, and any evaporation device in the technical field may be used, preferably a rotary evaporator is used to evaporate and remove most of the organic solvent. The present invention does not particularly limit the purification operation, and any purification method in the field may be used. Preferably, column chromatography is used, and the purification filler is 100 to 200 mesh silica gel. The present invention does not particularly limit the eluent used in column chromatography, and it may be any reagent in the art that achieves the purpose of elution. Preferably, the eluent is ethyl acetate/acetone. The volume ratio of ethyl acetate to acetone is preferably 2 to 6:1, particularly preferably 4:1.

第３の態様において、本発明は、前記第１の態様に記載の上記マグノロール誘導体、及び前記第２の態様に記載の方法で製造された上記マグノロール誘導体の静菌における使用をさらに提供する。 In a third aspect, the invention further provides the bacteriostatic use of the magnolol derivative according to the first aspect and the magnolol derivative produced by the method according to the second aspect. .

本発明で提供されたマグノロール誘導体は、食品、医薬品や化粧品に応用することができ、防腐剤又は防腐成分として使用することができ、従来の大腸菌、黄色ブドウ球菌、緑膿菌、カンジダ・アルビカンス、クロコウジカビなどに対して阻害作用を有する。好ましくは、前記マグノロール誘導体の使用量は、前記食品、医薬品や化粧品１ｇに対して０．００１～０．０１ｇである。 The magnolol derivatives provided by the present invention can be applied to foods, medicines and cosmetics, and can be used as preservatives or antiseptic ingredients, and can be used as a preservative for conventional Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans. It has an inhibitory effect on Aspergillus niger and Aspergillus niger. Preferably, the amount of the magnolol derivative used is 0.001 to 0.01 g per 1 g of the food, medicine, or cosmetic.

以下、実施例を用いて本発明を詳細に説明する。以下の実施例において、製造されたマグノロール誘導体の分子構造は、飛行時間質量分析計、核磁気共鳴分光計及び液体クロマトグラフ質量分析計により測定され、飛行質量分析計の型番はＨＲ ＥＩ－ＴＯＦＭＳであり、英国Ｋｏｒｅ社から購入され、核磁気共鳴分光計の型番はサーモフィッシャーのｐｉｃｏＳｐｉｎ８０であり、サーモフィッシャー社から購入され、液体クロマトグラフ質量分析計はＴＳＱ Ａｌｔｉｓ型の三連四重極質量分析計であり、サーモフィッシャー社から購入された。 Hereinafter, the present invention will be explained in detail using Examples. In the following examples, the molecular structure of the produced magnolol derivatives was determined by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer and a liquid chromatography mass spectrometer, and the model number of the flight mass spectrometer was HR EI-TOFMS. The model number of the nuclear magnetic resonance spectrometer was Thermo Fisher picoSpin80, and the liquid chromatograph mass spectrometer was a TSQ Altis type triple quadrupole mass spectrometer. It was purchased from Thermo Fisher.

以下の実施例において、特に説明がない限り、関連する原料はいずれも市販品であり、そのうち、植物由来のマグノロール含有量は９８％であり、湖南佳沐生物科技有限公司から購入され、使用したＮ－メチル－グリシン粉末、Ｎ－メチルアミノグリオキサールジエチルアセタールはすべて上海麦克林生物試薬有限公司から購入され、栄養ブロスは北京邁瑞達科技有限公司から購入され、主要な成分はペプトン、ビーフペースト、塩化ナトリウム及び水であり、サブロー培地は山東西亜化学工業有限公司から購入され、主要な成分はペプトンと寒天であり、ＴＴＣは２,３,５－トリフェニルテトラゾリウムクロライドの略称で、使用したＴＴＣ試薬は上海源叶生物科技有限公司から購入され、メチルパラベンは分析的に純粋なものであり、上海麦克林生化科技有限公司から購入され、フェノキシエタノールは分析的に純粋なものであり、上海アラジン生化科技股▲ふん▼有限公司から購入された。そのうち、大腸菌（Ｅｓｃｈｅｒｉｃｈｉａ ｃｏｌｉ）：ＡＴＣＣ ８７３９第４世代は、広東省微生物研究所から購入され、黄色ブドウ球菌（Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ）：ＡＴＣＣ ６５３８第４世代は、広東省微生物研究所から購入され、緑膿菌（Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ）：ＡＴＣＣ ９０２７第６世代は、広東省微生物研究所から購入され、カンジダ・アルビカンス（Ｃａｎｄｉｄａ ａｌｂｉｃａｎｓ）：ＡＴＣＣ８３２７第４世代は、広東省微生物研究所から購入され、クロコウジカビ（Ａｓｐｅｒｇｉｌｌｕｓ ｎｉｇｅｒ）：ＡＴＣＣ５４７８第４世代は、広東省微生物研究所から購入され、サブロー培地は山東西亜化学工業有限公司から購入される。 In the following examples, unless otherwise specified, all relevant raw materials are commercially available, of which the plant-based magnolol content is 98%, purchased from Hunan Jiamu Biotechnology Co., Ltd., and used. The N-methyl-glycine powder, N-methylaminoglyoxal diethyl acetal were all purchased from Shanghai Mukelin Biological Reagent Co., Ltd., and the nutritional broth was purchased from Beijing Yuruida Technology Co., Ltd., and the main ingredients were peptone, beef paste, Sabouraud medium was purchased from Shandong Xiya Chemical Industry Co., Ltd., the main components were peptone and agar, TTC is the abbreviation for 2,3,5-triphenyltetrazolium chloride, and the TTC used was The reagents were purchased from Shanghai Yuanyao Biotechnology Co., Ltd., methylparaben was analytically pure and purchased from Shanghai Mukelin Biochemical Technology Co., Ltd., and phenoxyethanol was analytically pure and purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. Purchased from crotch▲fun▼ Co., Ltd. Among them, Escherichia coli: ATCC 8739 4th generation was purchased from the Guangdong Provincial Microbiology Research Institute, and Staphylococcus aureus: ATCC 6538 4th generation was purchased from the Guangdong Provincial Microbiology Research Institute. Pseudomonas aeruginosa: ATCC 9027 6th generation was purchased from Guangdong Microbiology Research Institute, Candida albicans: ATCC 8327 4th generation was purchased from Guangdong Microbiology Research Institute, Aspergillus niger ): ATCC5478 4th generation is purchased from Guangdong Provincial Microbiology Research Institute, and Sabouraud medium is purchased from Shandong Xiya Chemical Industry Co., Ltd.

実施例１
まず、濃度１２ｍｏｌ／Ｌの塩酸１ｍｌをメタノール７０ｍｌに加えて、メタノールの酸溶液を調製して使用に備えた。
Ｎ－メチル－グリシン粉末７．６ｇを秤量して三口フラスコに投入し、３７質量％のホルムアルデヒド水溶液１０ｍｌを緩やかに滴下し、磁気撹拌を行い、滴下速度を１ｍｌ／ｍｉｎ、温度を３０～３５℃に制御した。氷水浴条件下、調製されたメタノールの酸溶液４０ｍｌを三口フラスコに加えて、滴下速度を４ｍｌ／ｍｉｎ、温度を２～５℃に制御し、滴下終了後、磁気撹拌を１ｈ持続し、第１接触により得られる生成物を得た。
マグノロール（含有量９８％）１３．３ｇを秤量して、残りのメタノールの酸溶液３０ｍｌに溶解し、マグノロールのメタノールの酸溶液を得た。第１接触により得られる生成物を容れた上記三口フラスコを油浴に入れて温度を７５℃に制御し、前記マグノロールのメタノールの酸溶液を加えて、凝縮して還流し、１０ｈ反応させた。その後、ロータリーエバポレータを用いて余分なメタノールを除去し、２００メッシュのシリカゲルカラムを用いて精製し、溶出液を体積比４：１の酢酸エチル／アセトンとし、得た溶出液を併せて濃縮し、その後、凍結乾燥し、マグノロール誘導体を得た。
反応原料中のマグノロールを基準に、収率は３５％であった。
飛行質量分析計及び核磁気共鳴分光計を用いてマグノロール誘導体を特徴付け、マグノロール誘導体の飛行質量スペクトルを図１、液体質量正イオン化図及び液体質量負イオン化図をそれぞれ図２及び図３に示す。ここで、図２における４６９のピーク及び図３における４６７のピークはマグノロール誘導体の特徴ピークを表し、図１～図３から分かるように、本実施例で製造された生成物は、本発明の式（１）で表される構造のマグノロール誘導体である。反応のメカニズムは以下のとおりである。 Example 1
First, 1 ml of hydrochloric acid having a concentration of 12 mol/L was added to 70 ml of methanol to prepare a methanol acid solution for use.
7.6 g of N-methyl-glycine powder was weighed and put into a three-necked flask, and 10 ml of a 37% by mass formaldehyde aqueous solution was slowly added dropwise thereto, followed by magnetic stirring at a dropping rate of 1 ml/min and a temperature of 30 to 35°C. was controlled. Under ice-water bath conditions, 40 ml of the prepared methanol acid solution was added to a three-necked flask, the dropping rate was 4 ml/min, the temperature was controlled at 2-5°C, and after the dropping, magnetic stirring was continued for 1 h. A product was obtained by contacting.
13.3 g of magnolol (98% content) was weighed and dissolved in the remaining 30 ml of methanol acid solution to obtain a methanol acid solution of magnolol. The three-necked flask containing the product obtained in the first contact was placed in an oil bath and the temperature was controlled at 75°C, and the methanol acid solution of the magnolol was added, condensed and refluxed, and reacted for 10 hours. . After that, excess methanol was removed using a rotary evaporator, purified using a 200 mesh silica gel column, the eluate was made into ethyl acetate/acetone at a volume ratio of 4:1, and the obtained eluates were concentrated together. Thereafter, it was freeze-dried to obtain a magnolol derivative.
The yield was 35% based on magnolol in the reaction raw materials.
We characterized the magnolol derivative using a flight mass spectrometer and a nuclear magnetic resonance spectrometer, and the flight mass spectrum of the magnolol derivative is shown in Figure 1, and the liquid mass positive ionization diagram and liquid mass negative ionization diagram are shown in Figures 2 and 3, respectively. show. Here, the peak 469 in FIG. 2 and the peak 467 in FIG. 3 represent characteristic peaks of magnolol derivatives, and as can be seen from FIGS. It is a magnolol derivative having a structure represented by formula (1). The reaction mechanism is as follows.

Figure 0007369864000011
Figure 0007369864000011

実施例２
まず、濃度１２ｍｏｌ／Ｌの塩酸１ｍｌをメタノール７０ｍｌに加えて、メタノールの酸溶液を調製して使用に備えた。
濃度４０重量％のジメチルアミン水溶液１１．３ｇを秤量して三口フラスコに投入し、３７質量％のホルムアルデヒド溶液１０ｍｌを緩やかに滴下し、磁気撹拌を行い、滴下速度を１ｍｌ／ｍｉｎ、温度を３０～３５℃に制御した。氷水浴条件下、三口フラスコに調製されたメタノールの酸溶液４０ｍｌを加えて、滴下速度を４ｍｌ／ｍｉｎ、温度を２～５℃に制御し、滴下終了後、磁気撹拌を１ｈ持続し、第１の接触により得られる生成物を得た。
マグノロール（含有量９８％）１３．３ｇを秤量して、残りのメタノールの酸溶液３０ｍｌに溶解し、マグノロールのメタノールの酸溶液を得た。第１接触により得られる生成物を容れた上記三口フラスコを油浴に入れて温度を７５℃に制御し、前記マグノロールのメタノールの酸溶液を加えて、凝縮して還流し、６ｈ反応させた。その後、ロータリーエバポレータを用いて余分なメタノールを除去し、２００メッシュのシリカゲルカラムを用いて精製し、溶出液を体積比４：１の酢酸エチル／アセトンとし、得た溶出液を併せて濃縮し、その後、凍結乾燥し、マグノロール誘導体を得た。
反応原料中のマグノロールを基準に、収率は６０％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体であることを確認した。反応のメカニズムは以下のとおりである。 Example 2
First, 1 ml of hydrochloric acid having a concentration of 12 mol/L was added to 70 ml of methanol to prepare a methanol acid solution for use.
Weighed out 11.3 g of a dimethylamine aqueous solution with a concentration of 40% by weight and put it into a three-necked flask, and slowly added 10ml of a 37% by weight formaldehyde solution dropwise, followed by magnetic stirring, with a dropping rate of 1ml/min and a temperature of 30~30% by weight. The temperature was controlled at 35°C. Under ice-water bath conditions, 40 ml of the prepared methanol acid solution was added to a three-necked flask, the dropping rate was 4 ml/min, the temperature was controlled at 2 to 5°C, and after the dropping, magnetic stirring was continued for 1 h. A product obtained by contacting was obtained.
13.3 g of magnolol (98% content) was weighed and dissolved in the remaining 30 ml of methanol acid solution to obtain a methanol acid solution of magnolol. The three-necked flask containing the product obtained in the first contact was placed in an oil bath and the temperature was controlled at 75°C, and the methanol acid solution of the magnolol was added, condensed and refluxed, and reacted for 6 hours. . After that, excess methanol was removed using a rotary evaporator, purified using a 200 mesh silica gel column, the eluate was made into ethyl acetate/acetone at a volume ratio of 4:1, and the obtained eluates were concentrated together. Thereafter, it was freeze-dried to obtain a magnolol derivative.
The yield was 60% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and the characterization results confirmed that the product produced in the example is a magnolol derivative having the structure represented by formula (1) of the present invention. . The reaction mechanism is as follows.

Figure 0007369864000012
Figure 0007369864000012

実施例３
まず、濃度１２ｍｏｌ／Ｌの塩酸１ｍｌをメタノール７０ｍｌに加えて、メタノールの酸溶液を調製して使用に備えた。
ジエタノールアミン１３ｇを秤量して三口フラスコに投入し、３７質量％のホルムアルデヒド溶液１０ｍｌを緩やかに滴下し、磁気撹拌を行い、滴下速度を１ｍｌ／ｍｉｎ、温度を３０～３５℃に制御した。氷水浴条件下、調製されたメタノールの酸溶液４０ｍｌを三口フラスコに加えて、滴下速度を４ｍｌ／ｍｉｎ、温度を２～５℃に制御し、滴下終了後、磁気撹拌を１ｈ持続し、第１の接触により得られる生成物を得た。
マグノロール（含有量９８％）１０ｇを秤量して、残りのメタノールの酸溶液３０ｍｌに溶解し、マグノロールのメタノールの酸溶液を得た。第１接触により得られる生成物を容れた上記三口フラスコを油浴に入れて温度を８５℃に制御し、前記マグノロールのメタノールの酸溶液を加えて、凝縮して還流し、６．５ｈ反応させた。その後、ロータリーエバポレータを用いて余分なメタノールを除去し、２００メッシュのシリカゲルカラムを用いて精製し、溶出液を体積比４：１の酢酸エチル／アセトンとし、得た溶出液を併せて濃縮し、その後、凍結乾燥し、マグノロール誘導体を得た。
反応原料中のマグノロールを基準に、収率は３５％であった。
飛行質量分析及び核磁気共鳴を使用して特徴付け、製造されたマグノロール誘導体の飛行質量スペクトルを図４、液体質量正イオン化図及び液体質量負イオン化図をそれぞれ図５及び図６、核磁気スペクトルを図７に示す。ここで、図５における５０１のピーク及び図６における４９９のピークは製造されたマグノロール誘導体の特徴ピークを表し、図４～図７から分かるように、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体である。反応のメカニズムは以下のとおりである。 Example 3
First, 1 ml of hydrochloric acid having a concentration of 12 mol/L was added to 70 ml of methanol to prepare a methanol acid solution for use.
13 g of diethanolamine was weighed and put into a three-necked flask, and 10 ml of a 37% by mass formaldehyde solution was slowly added dropwise thereto. Magnetic stirring was performed, and the dropping rate was controlled at 1 ml/min and the temperature was controlled at 30 to 35°C. Under ice-water bath conditions, 40 ml of the prepared methanol acid solution was added to a three-necked flask, the dropping rate was 4 ml/min, the temperature was controlled at 2-5°C, and after the dropping, magnetic stirring was continued for 1 h. A product obtained by contacting was obtained.
10 g of magnolol (98% content) was weighed and dissolved in the remaining 30 ml of methanol acid solution to obtain a methanol acid solution of magnolol. The three-necked flask containing the product obtained in the first contact was placed in an oil bath, the temperature was controlled at 85°C, and the methanol acid solution of magnolol was added, and the mixture was condensed and refluxed for 6.5 h of reaction. I let it happen. After that, excess methanol was removed using a rotary evaporator, purified using a 200 mesh silica gel column, the eluate was made into ethyl acetate/acetone at a volume ratio of 4:1, and the obtained eluates were concentrated together. Thereafter, it was freeze-dried to obtain a magnolol derivative.
The yield was 35% based on magnolol in the reaction raw materials.
The flight mass spectrum of the produced magnolol derivative characterized using flight mass spectrometry and nuclear magnetic resonance is shown in Figure 4, the liquid mass positive ionization diagram and the liquid mass negative ionization diagram in Figures 5 and 6, respectively, and the nuclear magnetic spectrum. is shown in Figure 7. Here, the peak 501 in FIG. 5 and the peak 499 in FIG. 6 represent characteristic peaks of the produced magnolol derivative, and as can be seen from FIGS. 4 to 7, the product produced in this example is It is a magnolol derivative having a structure represented by formula (1) of the invention. The reaction mechanism is as follows.

Figure 0007369864000013
Figure 0007369864000013

実施例４
実施例１の方法によって行われたが、マグノロールを加えず、同モル量の式（６）の構造のマグノロール系化合物を使用するとともに、式（６）の該マグノロール系化合物において、Ｒ1、Ｒ2、Ｒ3及びＲ4は順次に水素、塩素、メチル及びメトキシである以外、残りは実施例１と同様であった。
反応原料中のマグノロール系化合物を基準に、マグノロール誘導体の収率は２８％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次に水素、塩素、メチル及びメトキシであり、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次にメチル、

Figure 0007369864000014

メチル、
Figure 0007369864000015
であり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 4
It was carried out according to the method of Example 1, but without adding magnolol and using the same molar amount of the magnolol compound having the structure of formula (6), and in the magnolol compound having the structure of formula (6), R The rest was the same as in Example 1, except that 1 , R 2 , R 3 and R 4 were hydrogen, chlorine, methyl and methoxy, in order.
The yield of the magnolol derivative was 28% based on the magnolol compound in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are, in order, hydrogen, chlorine, methyl and methoxy; R 1 , R 2 , R 3 and R 4 are, in order, methyl,
Figure 0007369864000014
methyl,
Figure 0007369864000015
and R 5 , R 6 , R 7 and R 8 are all hydrogen).

実施例５
実施例２の方法によって行われたが、マグノロールを加えず、同モル量の式（６）の構造のマグノロール系化合物を使用するとともに、式（６）の該マグノロール系化合物において、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次に水素、塩素、メチル及びメチルフェニルである以外、残りは実施例２と同様であった。
反応原料中のマグノロール系化合物を基準に、マグノロール誘導体の収率は１７％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は、本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次に水素、塩素、メチル及びメチルフェニルであり、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべてメチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 5
The method was carried out according to the method of Example 2, but magnolol was not added and the same molar amount of the magnolol compound having the structure of formula (6) was used, and in the magnolol compound of formula (6), R The rest was the same as in Example 2, except that 1 , R 2 , R 3 and R 4 were, in order, hydrogen, chlorine, methyl and methylphenyl.
The yield of the magnolol derivative was 17% based on the magnolol compound in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative (herein, R 1 , R 2 , R 3 and R 4 are, in order, hydrogen, chlorine, methyl and methylphenyl, R 1 , R 2 , R 3 and R 4 are all methyl, R 5 , R 6 , R 7 and R 8 are all hydrogen).

実施例６
実施例２の方法によって行われたが、ジメチルアミンの代わりに同量のＮ－メチル－アミノエトキシエタノールを使用した以外、残りは実施例２と同様であった。
反応原料中のマグノロールを基準に、マグノロール誘導体の収率は４６％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべて水素であり、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次にメチル、

Figure 0007369864000016

メチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 6
It was carried out according to the method of Example 2, except that the same amount of N-methyl-aminoethoxyethanol was used instead of dimethylamine.
The yield of the magnolol derivative was 46% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are all hydrogen, and R 1 , R 2 , R 3 and R 4 are sequentially methyl,
Figure 0007369864000016
methyl, and R 5 , R 6 , R 7 and R 8 are all hydrogen).

実施例７
実施例２の方法によって行われたが、前記ジメチルアミンの代わりに同量のメチルアミノアセトアルデヒドジメチルアセタールを使用した以外、残りは実施例２と同様であった。
反応原料中のマグノロールを基準に、マグノロール誘導体の収率は３９％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべて水素であり、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次にメチル、

Figure 0007369864000017

メチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 7
It was carried out according to the method of Example 2, except that the same amount of methylaminoacetaldehyde dimethyl acetal was used instead of the dimethylamine.
The yield of the magnolol derivative was 39% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are all hydrogen, and R 1 , R 2 , R 3 and R 4 are sequentially methyl,
Figure 0007369864000017
methyl, and R 5 , R 6 , R 7 and R 8 are all hydrogen).

実施例８
実施例２の方法によって行われたが、ジメチルアミンを加えず、同モル量の式（２）で表される構造の化合物と式（４）で表される構造の化合物とを含有する混合物を使用し、前記式（２）で表される構造の化合物と式（４）で表される構造の化合物とのモル比は１：１であり、且つ式（２）及び式（４）中、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次にメチル、ｎ－オクチル、メチル、メチルである以外、残りは実施例２と同様であった。
反応原料中のマグノロールを基準に、マグノロール誘導体の収率は５１％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべて水素であり、Ｒ1、Ｒ2、Ｒ3及びＲ4は、順次にメチル、ｎ－オクチル、メチル、メチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 8
It was carried out by the method of Example 2, but dimethylamine was not added, and a mixture containing the same molar amount of the compound having the structure represented by formula (2) and the compound having the structure represented by formula (4) was used. The molar ratio of the compound having the structure represented by formula (2) and the compound having the structure represented by formula (4) is 1:1, and in formula (2) and formula (4), The rest was the same as in Example 2, except that R 1 , R 2 , R 3 and R 4 were, in order, methyl, n-octyl, methyl, methyl.
The yield of the magnolol derivative was 51% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are all hydrogen, R 1 , R 2 , R 3 and R 4 are, in order, methyl, n-octyl, methyl, methyl, R 5 , R 6 , R 7 and R 8 are all hydrogen).

実施例９
実施例２の方法によって行われたが、ジメチルアミン、ホルムアルデヒド及びマグノロールの使用量のモル比は６：６：１である以外、残りは実施例２と同様であった。
反応原料中のマグノロールを基準に、マグノロール誘導体の収率は４８％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべて水素であり、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべてメチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 9
The procedure was as in Example 2, except that the molar ratio of dimethylamine, formaldehyde and magnolol used was 6:6:1.
The yield of the magnolol derivative was 48% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are all hydrogen, R 1 , R 2 , R 3 and R 4 are all methyl, and R 5 , R 6 , R 7 and R 8 are all hydrogen) It was confirmed that

実施例１０
実施例２の方法によって行われたが、予めに塩酸とメタノールを調製しておらず、同量の第１の部分の塩酸とメタノールをそれぞれジメチルアミン溶液とホルムアルデヒドとの水溶液に直接加えて混合し、且つ残りの塩酸とメタノールを、マグノロール、第１接触により得られる生成物と直接混合して反応させた以外、残りは実施例２と同様であった。
反応原料中のマグノロールを基準に、マグノロール誘導体の収率は２４％であった。飛行質量分析及び核磁気共鳴を使用して特徴付け、特徴付け結果から、本実施例で製造された生成物は本発明の式（１）で表される構造のマグノロール誘導体（ここで、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべて水素であり、Ｒ1、Ｒ2、Ｒ3及びＲ4はすべてメチルであり、Ｒ5、Ｒ6、Ｒ7及びＲ8はすべて水素である）であることを確認した。 Example 10
It was carried out according to the method of Example 2, but hydrochloric acid and methanol were not prepared in advance, and the same amounts of hydrochloric acid and methanol of the first part were directly added to the aqueous solution of dimethylamine solution and formaldehyde, respectively, and mixed. The rest was the same as Example 2, except that the remaining hydrochloric acid and methanol were directly mixed and reacted with Magnolol, the product obtained from the first contact.
The yield of the magnolol derivative was 24% based on magnolol in the reaction raw materials. It was characterized using flight mass spectrometry and nuclear magnetic resonance, and from the characterization results, the product produced in this example is a magnolol derivative of the present invention having a structure represented by formula (1) (here, R 1 , R 2 , R 3 and R 4 are all hydrogen, R 1 , R 2 , R 3 and R 4 are all methyl, and R 5 , R 6 , R 7 and R 8 are all hydrogen) It was confirmed that

試験例１
溶解性の試験方法： メスシリンダを使用して２５±１℃で脱イオン水１００ｇを秤量し、ビーカー２５０ｍｌに入れた。磁気撹拌器に入れて、回転数を２００ｒｍｐ／ｍｉｎに調整した。分析天びんを用いてマグノロールをそれぞれ秤量し、実施例１～１０で製造されたマグノロール誘導体サンプルについて溶解性を試験し、試験に際して各サンプルを０．１ｇずつ脱イオン水に溶解し、１０分間撹拌しても完全に溶解できなくなると、最大溶解質量を記録した。結果を表１に示す。 Test example 1
Solubility test method: 100 g of deionized water at 25±1° C. was weighed into a 250 ml beaker using a graduated cylinder. It was placed in a magnetic stirrer and the rotation speed was adjusted to 200 rpm/min. Magnolol was individually weighed using an analytical balance and the magnolol derivative samples prepared in Examples 1 to 10 were tested for solubility; for testing, 0.1 g of each sample was dissolved in deionized water for 10 minutes. The maximum dissolved mass was recorded when complete dissolution could not be achieved even with stirring. The results are shown in Table 1.

試験例２
実施例１～１０で製造されたマグノロール誘導体のサンプルを試験対象とし、その最小静菌濃度ＭＩＣ値を定量的に試験した。１０重量％のマグノロールのエタノール溶液、従来の化学防腐剤であるメチルパラベン及びフェノキシエタノールを比較例とした。
最小静菌濃度ＭＩＣ値の試験方法：殺菌した栄養ブロス（大腸菌、黄色ブドウ球菌、緑膿菌培養用）、サブロー培地（カンジダ・アルビカンス、クロコウジカビ培養用）を希釈液として、二倍希釈法により試験サンプルを希釈し、その後、それぞれ表２で表される濃度で対応する菌を接種した。細菌を３５℃で３６ｈ培養し、真菌を２８℃で４８ｈ培養した。培養終点よりも３ｈ前に、ＴＴＣ試薬を加えて培養し続け、培養が赤くなると、この濃度では微生物の成長を阻害できず、培養液が赤くなっていないと、赤くなっていない培養液中の最小薬剤濃度がこの微生物に対する静菌剤の最小静菌濃度であると考えられた。具体的には、結果を表３に示す。 Test example 2
Samples of magnolol derivatives produced in Examples 1 to 10 were tested, and their minimum bacteriostatic concentration MIC values were quantitatively tested. A 10% by weight ethanolic solution of magnolol, conventional chemical preservatives methylparaben and phenoxyethanol were used as comparative examples.
Test method for minimum bacteriostatic concentration MIC value: Using sterilized nutrient broth (for culturing Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa) and Sabouraud medium (for culturing Candida albicans and Aspergillus niger) as a diluent, by the two-fold dilution method. The test samples were diluted and then inoculated with the corresponding bacteria at the concentrations shown in Table 2, respectively. Bacteria were cultured at 35°C for 36 h, and fungi were cultured at 28°C for 48 h. 3 hours before the end of the culture, add TTC reagent and continue culturing, and if the culture becomes red, this concentration cannot inhibit the growth of microorganisms, and if the culture solution does not turn red, The minimum drug concentration was considered to be the minimum bacteriostatic concentration of the bacteriostatic agent against this microorganism. Specifically, the results are shown in Table 3.

試験例３
実施例１～１０で製造されたマグノロール誘導体を、以下の表４の噴霧処方又は類似の噴霧処方に添加した。一定量の細菌及び真菌を接種し、０日、７日、１４日、２１日、２８日おきに米国薬局方ＵＳＰ３２＜５１＞における微生物防腐効果試験の検出方法に従って微生物の数の変化を検出した。ここで、実施例２（表４における噴霧処方を参照し、実施例２で製造されたマグノロール誘導体を用い、かつ添加量を０．５重量％とした）、実施例３（以下の表４の噴霧処方を使用）、実施例６（表４の噴霧処方を参照し、実施例６で製造されたマグノロール誘導体を用い、且つ添加量を０．５重量％とした）及び実施例１０（表４の噴霧処方を参照し、実施例１０で製造されたマグノロール誘導体を用い、かつ添加量を１重量％とした）で製造されたマグノロール誘導体の試験結果は以下の表５に示され、残りの実施例１、実施例４～５、及び実施例７～９で製造されたマグノロール誘導体の試験結果（すべて以下の表４の噴霧処方を用いた）は類似しており、すべて検出した結果、合格であった。 Test example 3
The magnolol derivatives prepared in Examples 1-10 were added to the spray formulations in Table 4 below or similar spray formulations. A certain amount of bacteria and fungi were inoculated, and changes in the number of microorganisms were detected every 0, 7, 14, 21, and 28 days according to the detection method of microbial preservative effect test in United States Pharmacopoeia USP 32 <51>. . Here, Example 2 (referring to the spray formulation in Table 4, using the magnolol derivative produced in Example 2, and the addition amount was 0.5% by weight), Example 3 (seeing Table 4 below) Example 6 (using the spray formulation in Table 4, using the magnolol derivative produced in Example 6, and adding an amount of 0.5% by weight) and Example 10 ( Referring to the spray formulation in Table 4, using the magnolol derivative manufactured in Example 10, and with an addition amount of 1% by weight, the test results of the magnolol derivative are shown in Table 5 below. The test results for the remaining magnolol derivatives prepared in Example 1, Examples 4-5, and Examples 7-9 (all using the spray formulations in Table 4 below) were similar and all detected As a result, I passed the exam.

Figure 0007369864000018
Figure 0007369864000018

Figure 0007369864000019
Figure 0007369864000019

Figure 0007369864000020
Figure 0007369864000020

Figure 0007369864000021
Figure 0007369864000021

Figure 0007369864000022
Figure 0007369864000022

表１の結果から分かるように、溶解度定性試験において、本発明で製造されたマグノロール誘導体は１００ｇの溶媒水においていずれも良い溶解性を有し、このうち、実施例２、実施例９及び実施例１０で製造されたマグノロール誘導体の溶媒水１００ｇにおける溶解度は１ｇより大きく、すなわち、これらの実施例で製造されたサンプルはすべて溶解し、一方、植物から抽出されたマグノロールは水に不溶であった。 As can be seen from the results in Table 1, in the qualitative solubility test, the magnolol derivatives produced according to the present invention all had good solubility in 100 g of solvent water. The solubility of the magnolol derivative prepared in Example 10 in 100 g of solvent water is greater than 1 g, i.e., all the samples prepared in these examples are soluble, whereas the magnolol extracted from plants is insoluble in water. there were.

表３のデータから明らかなように、実施例１～１０で製造されたマグノロール誘導体は、大腸菌、黄色ブドウ球菌、緑膿菌、カンジダ・アルビカンス、クロコウジカビに対して優れた静菌作用を有し、特に実施例１～３、実施例６、及び実施例８～１０は顕著な静菌作用があり、しかも静菌効果は、従来の化学防腐剤であるメチルパラベンとフェノキシエタノールより優れている。 As is clear from the data in Table 3, the magnolol derivatives produced in Examples 1 to 10 have excellent bacteriostatic activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. However, Examples 1 to 3, Example 6, and Examples 8 to 10 in particular have a remarkable bacteriostatic effect, and the bacteriostatic effect is superior to conventional chemical preservatives such as methylparaben and phenoxyethanol.

表４の噴霧処方は、細菌や真菌の生存に非常に適した環境を提供し、表５のデータから明らかなように、このような過酷な条件下では、本発明の実施例２、実施例３、実施例６及び実施例１０で製造されたサンプルは優れた静菌能力を示し、２８日間のミスト状水剤処方のチャレンジテストを経たところ、実施例２、実施例３、実施例６及び実施例１０のマグノロール誘導体は防腐剤としてチャレンジテストに合格し、他の実施例は効果が類似している。 The spray formulation in Table 4 provides a very suitable environment for the survival of bacteria and fungi, and as is clear from the data in Table 5, under such harsh conditions, the spray formulation of the present invention, Example 2, Example 3. The samples produced in Example 6 and Example 10 showed excellent bacteriostatic ability, and after a 28-day challenge test of mist formulation, the samples produced in Example 2, Example 3, Example 6 and The magnolol derivative of Example 10 passes the challenge test as a preservative, and the other examples are similar in effectiveness.

マグノロール自体は水に溶解しないため、静菌効果を測定することは困難である。１０重量％のマグノロールのエタノール溶液の静菌効果は非常に良いが、国家基準では化粧品中のエタノールの使用量に対して厳格な規制があり、しかも水系に応用すると、マグノロールはエタノールから析出するので、工業的に応用することができない。 Since magnolol itself is not soluble in water, it is difficult to measure its bacteriostatic effect. The bacteriostatic effect of a 10% by weight ethanol solution of Magnolol is very good, but national standards have strict regulations on the amount of ethanol used in cosmetics, and when applied to aqueous systems, Magnolol precipitates from the ethanol. Therefore, it cannot be applied industrially.

本発明の方法を用いてマグノロールを変性して得られるマグノロール誘導体は、水溶性が良好であり、マグノロールの水における溶解度を効果的に向上させ、マグノロール誘導体は、よく見られるグラム陰性菌、グラム陽性菌、真菌などに対して顕著な阻害効果がある。 The magnolol derivative obtained by modifying magnolol using the method of the present invention has good water solubility and effectively improves the solubility of magnolol in water. It has a remarkable inhibitory effect on bacteria, gram-positive bacteria, fungi, etc.

以上、本発明の好適な実施形態について詳細に説明したが、本発明はこれに限定されるものではない。本発明の技術的概念の範囲内では、個々の技術的特徴を他の任意の適切な方法で組み合わせることを含め、本発明の技術的解決手段に対して複数の簡単な変形を行うことができ、これらの簡単な変形及び組み合わせは、同様に本発明に開示されたものとみなされ、いずれも本発明の特許範囲に属する。 Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited thereto. Within the scope of the technical concept of the invention, several simple variations can be made to the technical solution of the invention, including combining the individual technical features in any other suitable way. , these simple variations and combinations are also considered to be disclosed in the present invention, and all fall within the patent scope of the present invention.

Claims (18)

以下の化合物から選択される少なくとも１種であるマグノロール誘導体。
Figure 0007369864000023
Figure 0007369864000024
Figure 0007369864000025
 A magnolol derivative that is at least one selected from the following compounds.
Figure 0007369864000023
Figure 0007369864000024
Figure 0007369864000025
 マグノロール誘導体の製造方法であって、
マンニッヒ反応の条件下で、式（２）又は式（４）の構造を有する化合物と式（３）又は式（５）の構造を有する化合物との第１接触を行い、その後、第１接触により得られる生成物と式（６）の構造を有する化合物との第２接触を行い、マンニッヒ反応生成物を得ることを含み、
前記第１接触及び前記第２接触とも、酸性物質及び溶媒の存在下で行い、
前記式（２）又は前記式（４）の構造を有する化合物は、Ｎ－メチル－グリシン、ジエタノールアミン、ジメチルアミンのいずれか１つから選択され、
前記式（３）又は前記式（５）の構造を有する化合物はホルムアルデヒドであることを特徴とするマグノロール誘導体の製造方法。
Figure 0007369864000026
 A method for producing a magnolol derivative, comprising:
A first contact between a compound having the structure of formula (2 ) or formula (4) and a compound having the structure of formula (3 ) or formula (5) is carried out under Mannich reaction conditions, and then the first contact is carried out under Mannich reaction conditions. carrying out a second contact of the product obtained by the contact with a compound having the structure of formula (6) to obtain a Mannich reaction product ,
Both the first contact and the second contact are performed in the presence of an acidic substance and a solvent,
The compound having the structure of the formula (2) or the formula (4) is selected from any one of N-methyl-glycine, diethanolamine, and dimethylamine,
A method for producing a magnolol derivative , wherein the compound having the structure of the formula (3) or the formula (5) is formaldehyde .
Figure 0007369864000026
 前記式（２）又は前記式（４）の構造を有する化合物の総量と、前記式（３）又は前記式（５）の構造を有する化合物の総量と、前記式（６）の構造を有する化合物とのモル比が０．５～６：０．５～６：１である、請求項２に記載の方法。 The total amount of the compound having the structure of the formula (2 ) or the formula (4), the total amount of the compound having the structure of the formula (3 ) or the formula (5), and the structure of the formula (6). The method according to claim 2 , wherein the molar ratio with the compound having the compound is 0.5 to 6:0.5 to 6:1. 前記式（２）又は前記式（４）の構造を有する化合物の総量と、前記式（３）又は前記式（５）の構造を有する化合物の総量と、前記式（６）の構造を有する化合物とのモル比が１～４：１～４：１である、請求項３に記載の方法。 The total amount of the compound having the structure of the formula (2 ) or the formula (4), the total amount of the compound having the structure of the formula (3 ) or the formula (5), and the structure of the formula (6). 4. The method according to claim 3 , wherein the molar ratio of the compound with the compound is from 1 to 4:1 to 4:1. 前記マンニッヒ反応条件には、前記第１接触の温度が１～５０℃であることと、前記第２接触の温度が３０～９０℃であることとが含まれる、請求項２～４のいずれか１項に記載の方法。 Any one of claims 2 to 4 , wherein the Mannich reaction conditions include that the temperature of the first contact is 1 to 50°C, and the temperature of the second contact is 30 to 90°C. The method described in Section 1 . 前記マンニッヒ反応条件には、前記第１接触の温度が２～５０℃であることと、前記第２接触の温度が７０～８５℃であることが含まれる、請求項５に記載の方法。 6. The method of claim 5 , wherein the Mannich reaction conditions include a temperature of the first contact being 2 to 50°C and a temperature of the second contact being 70 to 85°C. 前記マンニッヒ反応条件には、前記第１接触の時間が５ｍｉｎ～２ｈであることと、前記第２接触の時間が１～２０ｈであることとがさらに含まれる、請求項２～６のいずれか１項に記載の方法。 Any one of claims 2 to 6, wherein the Mannich reaction conditions further include that the first contact time is 5 min to 2 h, and the second contact time is 1 to 20 h. The method described in section . 前記マンニッヒ反応条件には、前記第１接触の時間が１０ｍｉｎ～２ｈであることと、前記第２接触の時間が５～１０ｈであることとがさらに含まれる、請求項７に記載の方法。 8. The method of claim 7 , wherein the Mannich reaction conditions further include that the first contact time is 10 min to 2 h, and the second contact time is 5 to 10 h. 前記酸性物質が、塩酸、リン酸、硫酸及び酢酸から選択される少なくとも１種である、請求項２～８のいずれか１項に記載の方法。 The method according to any one of claims 2 to 8 , wherein the acidic substance is at least one selected from hydrochloric acid, phosphoric acid, sulfuric acid, and acetic acid. 前記溶媒が水及び／又は有機溶媒である、請求項２～９のいずれか１項に記載の方法。 The method according to any one of claims 2 to 9 , wherein the solvent is water and/or an organic solvent. 前記有機溶媒が、メタノール、エタノール、イソプロパノール及び酢酸から選択される少なくとも１種である、請求項１０に記載の方法。 The method according to claim 10 , wherein the organic solvent is at least one selected from methanol, ethanol, isopropanol, and acetic acid. 前記有機溶媒が、メタノール及び／又はエタノールである、請求項１１に記載の方法。 The method according to claim 11 , wherein the organic solvent is methanol and/or ethanol. 前記式（２）又は前記式（４）の構造を有する化合物、前記式（３）又は前記式（５）の構造を有する化合物、及び前記式（６）の構造を有する化合物の総量に対して、前記酸性物質の使用量が０．０３～１０ｍＬ／ｇであり、前記溶媒の使用量が２～１５ｍＬ／ｇである、請求項２～１２のいずれか１項に記載の方法。 The total amount of the compound having the structure of the above formula (2 ) or the above formula (4), the compound having the structure of the above formula (3 ) or the above formula (5), and the compound having the structure of the above formula (6) On the other hand, the method according to any one of claims 2 to 12 , wherein the amount of the acidic substance used is 0.03 to 10 mL/g, and the amount of the solvent used is 2 to 15 mL/g. 前記第１接触の方式が、２０～５０℃で前記式（３）又は前記式（５）の構造を有する化合物を前記式（２）又は前記式（４）の構造を有する化合物に加え、その後、１～１０℃で酸性物質又は酸性物質の前記溶媒における溶液を加え、反応を０．５～２ｈ持続することを含む、請求項２～１３のいずれか１項に記載の方法。 The first contact method includes adding a compound having the structure of the formula (3 ) or the formula (5) to the compound having the structure of the formula (2 ) or the formula (4) at 20 to 50°C. , followed by adding an acidic substance or a solution of an acidic substance in said solvent at 1 to 10°C and continuing the reaction for 0.5 to 2 h. 前記第２接触の方式が、前記式（６）の構造を有する化合物を前記酸性物質の存在下で前記溶媒に溶解して溶液を形成し、その後、前記第１接触により得られる生成物と３０～９０℃で前記第２接触を行うことを含む、請求項２～１４のいずれか１項に記載の方法。 The method of the second contact includes dissolving the compound having the structure of formula (6) in the solvent in the presence of the acidic substance to form a solution, and then forming a solution with the product obtained by the first contact. A method according to any one of claims 2 to 14 , comprising carrying out the second contact at 30-90°C. 非疾患における請求項１に記載のマグノロール誘導体の静菌のための使用。 Use of a magnolol derivative according to claim 1 for bacteriostatic purposes in non-diseases . 前記菌が、大腸菌、黄色ブドウ球菌、緑膿菌、カンジダ・アルビカンス、及びクロコウジカビから選択される少なくとも１種である、請求項１６に記載の使用。 The use according to claim 16 , wherein the bacterium is at least one selected from Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. 前記菌が、食品、医薬品又は化粧品に存在し、食品、医薬品又は化粧品１ｇに対して、前記マグノロール誘導体の使用量が０．００１～０．０１ｇである、請求項１６又は１７に記載の使用。 The use according to claim 16 or 17 , wherein the bacteria are present in food, medicine, or cosmetics, and the amount of the magnolol derivative used is 0.001 to 0.01 g per 1 g of food, medicine, or cosmetics. .
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