JP2001253879A - Alkyl derivative of catechins - Google Patents
Alkyl derivative of catechinsInfo
- Publication number
- JP2001253879A JP2001253879A JP2000112742A JP2000112742A JP2001253879A JP 2001253879 A JP2001253879 A JP 2001253879A JP 2000112742 A JP2000112742 A JP 2000112742A JP 2000112742 A JP2000112742 A JP 2000112742A JP 2001253879 A JP2001253879 A JP 2001253879A
- Authority
- JP
- Japan
- Prior art keywords
- catechin
- gallate
- bioactivity
- alkyl
- epigallocatechin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Pyrane Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、茶カテキン類の本来有
する優れた生物活性を長時間にわたって保持し、かつ安
定性を有し、抗酸化性、アポトーシス誘導作用および抗
アレルギー作用を有するカテキン誘導体に関する。FIELD OF THE INVENTION The present invention relates to a catechin derivative having a long-lasting, excellent biological activity inherent in tea catechins, having stability, and having antioxidant, apoptosis-inducing and antiallergic effects. About.
【０００２】[0002]
【従来の技術】従来、カメリア シネンシス（Ｃａｍｅ
ｌｌｉａ ｓｉｎｅｎｓｉｓ Ｌ．）の葉からエピガロ
カテキン−３−Ｏ−（３−Ｏ−メチル）ガレートおよび
エピカテキン−３−Ｏ−（３−Ｏ−メチル）ガレートを
取得する方法［Ｒ．Ｓａｉｊｏ等著、Ａｇｒｉｃ．Ｂｉ
ｏｌ．Ｃｈｅｍ．，ｖｏｌ．４６，１９６９（１９８
２）］、エピガロカテキン−３−Ｏ−（４−Ｏ−メチ
ル）ガレート［Ｍ．Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．Ｆ
ｏｏｄ Ｃｈｅｍ．，ｖｏｌ．４７，１９０６（１９９
９）］等の天然物から抽出分離して得る方法が知られて
いる。2. Description of the Related Art Conventionally, Camellia sinensis (Came)
llia sinensis L. )) To obtain epigallocatechin-3-O- (3-O-methyl) gallate and epicatechin-3-O- (3-O-methyl) gallate from leaves [R. Saijo et al., Agric. Bi
ol. Chem. , Vol. 46, 1969 (198
2)], epigallocatechin-3-O- (4-O-methyl) gallate [M. Sano et al. Agric. F
wood Chem. , Vol. 47, 1906 (199
9)] and the like, which are obtained by extraction and separation from natural products.
【０００３】[0003]
【発明が解決する課題】カテキン類の水酸基を全てアル
キル化する方法は知られているが、カテキン類の水酸基
を部分的にアルキル化する方法は知られていない。A method of alkylating all the hydroxyl groups of catechins is known, but a method of partially alkylating the hydroxyl groups of catechins is not known.
【０００４】エピガロカテキン−３−Ｏ−（３−Ｏ−メ
チル）ガレートやエピガロカテキン−３−Ｏ−（４−Ｏ
−メチル）ガレートのようなエピガロカテキン−３−Ｏ
−ガレートの部分アルキル化体はエピガロカテキン−３
−Ｏ−ガレートと同様に抗酸化作用、抗アレルギー
作用、アポトーシス誘導作用など、食品および医薬産
業上重要な物質である。Epigallocatechin-3-O- (3-O-methyl) gallate and epigallocatechin-3-O- (4-O
-Epigallocatechin-3-O, such as -methyl) gallate
-Partially alkylated gallate is epigallocatechin-3
Like O-gallate, it is an important substance in the food and pharmaceutical industries, such as an antioxidant action, an antiallergic action, and an apoptosis-inducing action.
【０００５】しかしながら、エピガロカテキン−３−Ｏ
−（４−Ｏ−メチル）ガレートは特殊な茶葉にのみ含有
される物質で含有量も少なく多量に収得することは困難
である。[0005] However, epigallocatechin-3-O
-(4-O-methyl) gallate is a substance contained only in special tea leaves and has a low content, making it difficult to obtain a large amount.
【０００６】[0006]
【課題を解決するための手段】そこで本発明者等はこの
ような問題を解決するため、種々検討を重ねた結果、炭
酸リチウムの存在下で、カテキン類をアルキルハライド
と反応させることによって、カテキン類の有する優れた
生物活性をほとんど損なうことなく、高収量で安定なカ
テキン誘導体を容易に製造する方法を発明した。In order to solve such a problem, the present inventors have made various studies. As a result, catechins are reacted with alkyl halides in the presence of lithium carbonate to obtain catechins. The present inventors have invented a method for easily producing a stable and high-yield catechin derivative without substantially impairing the excellent biological activity of the class.
【発明の実施の形態】炭酸リチウムを触媒としアルキル
ハライドでアルキル化する。アルキルハライドとしては
通常使用しているものを使用することができ、たとえ
ば、炭素数１−１０のアルキルアイオダイド、具体的に
は、ヨウ化メチル、ヨウ化エチル、ヨウ化ブチル、ヨウ
化プロピルなどが好ましく例示でき、なかでもヨウ化メ
チルが、一般性とコストの面から特に好ましい。BEST MODE FOR CARRYING OUT THE INVENTION Alkylation with an alkyl halide is carried out using lithium carbonate as a catalyst. As the alkyl halide, those usually used can be used. For example, alkyl iodides having 1 to 10 carbon atoms, specifically, methyl iodide, ethyl iodide, butyl iodide, propyl iodide and the like can be used. And methyl iodide is particularly preferred from the viewpoint of generality and cost.
【０００７】すなわち本発明は、一般式（１）で表され
るカテキン誘導体を提供するものである。That is, the present invention provides a catechin derivative represented by the general formula (1).
【０００８】[0008]
【化２】 （式中、Ｒ１〜Ｒ７の少なくとも１つは炭素数１−１０
のアルキル残基を示し、Ｒ８はＨまたはＯＨ、他は各々
独立にＨまたはβ−Ｄ−グルコース残基を示す）Embedded image (Wherein at least one of R 1 to R 7 has 1 to 10 carbon atoms)
R 8 represents H or OH, and the others each independently represent H or β-D-glucose residue.
【０００９】以下、本発明を詳細に説明する。まず、本
発明を実施するためには、カテキン類を炭酸リチウム存
在下にアルキルハライドのジメチルホルムアミド溶液と
反応を行わせる。Hereinafter, the present invention will be described in detail. First, in order to carry out the present invention, catechins are reacted with a dimethylformamide solution of an alkyl halide in the presence of lithium carbonate.
【００１０】また、反応に使用する炭酸リチウムは２モ
ル等量、アルキルハライドは５モル等量で、反応時間は
５〜１００時間、望ましくは２０時間、反応温度は１０
〜７０℃、望ましくは２０℃である。In addition, lithium carbonate used in the reaction is 2 molar equivalents, alkyl halide is 5 molar equivalents, and the reaction time is 5 to 100 hours, preferably 20 hours, and the reaction temperature is 10 hours.
To 70 ° C, preferably 20 ° C.
【００１１】このようにして得られた反応液から、目的
とするカテキン誘導体の分離は、通常希酸で反応液を酸
性とした後、多量の水で希釈しダイアイオンＨＰ−２０
等のポリスチレン系多孔質樹脂を担体とするクロマトグ
ラフィー法［Ｍ．Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．Ｆｏ
ｏｄＣｈｅｍ．，ｖｏｌ．４７，１９０６（１９９
９）］、セファデックスＬＨ−２０等のデキストラン誘
導体を担体とするクロマトグラフィー法［Ｆ．Ｈａｓｈ
ｉｍｏｔｏ等著、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，
ｖｏｌ．３７，３２５５（１９８９）］、逆相シリカゲ
ルを用いた液体クロマトグラフィー法［Ｆ．Ｈａｓｈｉ
ｍｏｔｏ等著、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，ｖ
ｏｌ．３７，３２５５（１９８９）］、順相シリカゲル
を用いた液体クロマトグラフィー法［Ｇ．Ｎｏｎａｋａ
等著、Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，ｖｏｌ．２
９，２８６２（１９８１）］を単独又は組み合わせて採
用すればよい。The desired catechin derivative is separated from the reaction solution obtained as described above, usually by acidifying the reaction solution with a dilute acid and then diluting it with a large amount of water to obtain a DIAION HP-20.
Chromatographic method using a polystyrene-based porous resin as a carrier [M. Sano et al. Agric. Fo
odChem. , Vol. 47, 1906 (199
9)], a chromatography method using a dextran derivative such as Sephadex LH-20 as a carrier [F. Hash
Imoto et al., Chem. Pharm. Bull. ,
vol. 37, 3255 (1989)], a liquid chromatography method using reversed-phase silica gel [F. Hashi
Moto et al., Chem. Pharm. Bull. , V
ol. 37, 3255 (1989)], a liquid chromatography method using normal phase silica gel [G. Nonaka
Et al., Chem. Pharm. Bull. , Vol. 2
9, 2862 (1981)] alone or in combination.
【００１２】[0012]
【実施例】（実施例１）（−）−エピガロカテキン−３
−Ｏ−ガレート１．００ｇを１０ｍｌのジメチルフォル
ムアミドに溶解し、これに炭酸リチウム５００ｍｇ、ヨ
ウ化メチル３．０ｍｌを加え、反応容器内を窒素ガスで
置換した後室温で２４時間攪拌する。反応液は希塩酸に
て酸性とし１０倍量の水で希釈する。これを、ダイアイ
オンＨＰ−２０（三菱化学社製）１４０ｍｌを充填した
カラムクロマトグラフィーに付し、水１０００ｍｌでカ
ラムを洗浄した後、メタノール５００ｍｌで溶出する。
ここに得たメタノール溶出液を濃縮後、高速液体クロマ
トグラフィー法［Ｍ．Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．
Ｆｏｏｄ Ｃｈｅｍ．，ｖｏｌ．４７，１９０６（１９
９９）］にて反応生成物を分離精製する。EXAMPLES (Example 1) (-)-Epigallocatechin-3
1.00 g of -O-gallate is dissolved in 10 ml of dimethylformamide, and 500 mg of lithium carbonate and 3.0 ml of methyl iodide are added thereto. After the inside of the reaction vessel is replaced with nitrogen gas, the mixture is stirred at room temperature for 24 hours. The reaction solution is made acidic with diluted hydrochloric acid and diluted with 10 times the volume of water. This was subjected to column chromatography packed with 140 ml of Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), and the column was washed with 1000 ml of water and eluted with 500 ml of methanol.
After concentrating the methanol eluate obtained here, high-performance liquid chromatography [M. Sano et al. Agric.
Food Chem. , Vol. 47, 1906 (19
99)] to separate and purify the reaction product.
【００１３】上記の分離条件は、 カラム：ＯＤＳ 内径５ｃｍ、長さ１００ｃｍ 流速：４５ｍｌ／ｍｉｎ 移動相：アセトニトリルー水 （１３：８７） 検出波長：２８０ｎｍThe above separation conditions are as follows: Column: ODS inner diameter 5 cm, length 100 cm Flow rate: 45 ml / min Mobile phase: acetonitrile water (13:87) Detection wavelength: 280 nm
【００１４】このようにして、分離精製を行うと、保持
時間２．７時間に未反応の（−）−エピガロカテキン−
３−Ｏ−ガレート１１４ｍｇを、保持時間４．０時間に
（−）−エピガロカテキン−３−Ｏ−（４−Ｏ−メチ
ル）ガレート３６５ｍｇを得た。When the separation and purification are performed as described above, unreacted (-)-epigallocatechin- has a retention time of 2.7 hours.
114 mg of 3-O-gallate and 365 mg of (-)-epigallocatechin-3-O- (4-O-methyl) gallate were obtained at a retention time of 4.0 hours.
【００１５】その構造を以下の核磁気共鳴法及び旋光度
の測定により、それぞれの構造を確認した。The structure was confirmed by the following nuclear magnetic resonance method and measurement of optical rotation.
【００１６】[0016]
【化３】 Embedded image
【００１７】[0017]
【化４】 Embedded image
【００１８】エピガロカテキン−３−Ｏ−（４−Ｏ−メ
チル）ガレートの旋光度、１Ｈ−ＮＭＲおよび１３Ｃ−
ＮＭＲ ［α］Ｄ ２３−１５６．６°（ｃ＝０．９，ＭｅＯ
Ｈ）．１Ｈ−ＮＭＲ（ａｃｅｔｏｎｅ−ｄ６）：δ２．
９３（１Ｈ，ｄｄ，Ｊ＝１７．５，２．５Ｈｚ，Ｈ−
４），３．０４（１Ｈ，ｄｄ，Ｊ＝１７．５，４．５Ｈ
ｚ，Ｈ−４），３．８３（３Ｈ，ｓ，ＯＭｅ），５．０
６（１Ｈ，ｂｒ ｓ，Ｈ−２），５．５４（１Ｈ，ｍ，
Ｈ−３），６．０３（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ，Ｈ−
８），６．０５（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ，Ｈ−
６），６．６４（２Ｈ，ｂｒ ｓ，Ｈ−２’，Ｈ−
６’），７．００（２Ｈ，ｓ，Ｈ−２”，Ｈ−６”）．
１３Ｃ−ＮＭＲ（ａｃｅｔｏｎｅ−ｄ６）：δ ２６．
５（Ｃ−４），６０．５（ＯＭｅ），６９．８（Ｃ−
３），７８．０（Ｃ−２），９５．７（Ｃ−８），９
６．４（Ｃ−６），９８．８（Ｃ−４ａ），１０６．６
（Ｃ−２’，Ｃ−６’），１０９．９（Ｃ−２”，Ｃ−
６”），１２６．４（Ｃ−１”），１３０．７（Ｃ−
１’），１３３．０（Ｃ−４’），１４０．５（Ｃ−
４”），１４６．２（Ｃ−３’，Ｃ−５’），１５１．
０（Ｃ−３”，Ｃ−５”），１５７．０（Ｃ−８ａ），
１５７．４（Ｃ−５），１５７．８（Ｃ−７），１６
６．０（Ｃ−α）．Optical rotation, 1 H-NMR and 13 C-NMR of epigallocatechin-3-O- (4-O-methyl) gallate
NMR [α] D 23 -156.6 ° (c = 0.9, MeO
H). 1 H-NMR (acetone-d 6 ): δ2.
93 (1H, dd, J = 17.5, 2.5 Hz, H-
4), 3.04 (1H, dd, J = 17.5, 4.5H)
z, H-4), 3.83 (3H, s, OMe), 5.0.
6 (1H, brs, H-2), 5.54 (1H, m,
H-3), 6.03 (1H, d, J = 2.5 Hz, H-
8), 6.05 (1H, d, J = 2.5 Hz, H-
6), 6.64 (2H, brs, H-2 ', H-
6 '), 7.00 (2H, s, H-2 ", H-6").
13 C-NMR (acetone-d 6 ): δ 26.
5 (C-4), 60.5 (OMe), 69.8 (C-
3), 78.0 (C-2), 95.7 (C-8), 9
6.4 (C-6), 98.8 (C-4a), 106.6
(C-2 ', C-6'), 109.9 (C-2 ", C-
6 "), 126.4 (C-1"), 130.7 (C-
1 '), 133.0 (C-4'), 140.5 (C-
4 "), 146.2 (C-3 ', C-5'), 151.
0 (C-3 ", C-5"), 157.0 (C-8a),
157.4 (C-5), 157.8 (C-7), 16
6.0 (C-α).
【００１９】（実施例２）エピカテキン−３−Ｏ−ガレ
ート４４．２ｍｇを２ｍｌのジメチルフォルムアミドに
溶解し、これに炭酸リチウム１８ｍｇ、ヨウ化メチル
０．１ｍｌを加え、反応容器内を窒素ガスで置換した後
室温で２０時間攪拌する。反応液は希塩酸にて酸性とし
１０倍量の水で希釈する。これを、ダイアイオンＨＰ−
２０（三菱化学社製）１２ｍｌを充填したカラムクロマ
トグラフィーに付し、水１００ｍｌでカラムを洗浄した
後、メタノール５０ｍｌで溶出する。ここに得たメタノ
ール溶出液を濃縮後、高速液体クロマトグラフィー法
［Ｍ．Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．Ｆｏｏｄ Ｃｈ
ｅｍ．，ｖｏｌ．４７，１９０６（１９９９）］にて反
応生成物を分離精製する。Example 2 44.2 mg of epicatechin-3-O-gallate was dissolved in 2 ml of dimethylformamide, and 18 mg of lithium carbonate and 0.1 ml of methyl iodide were added thereto. And stirred at room temperature for 20 hours. The reaction solution is made acidic with diluted hydrochloric acid and diluted with 10 times the volume of water. This is called Diaion HP-
After column chromatography packed with 12 ml of 20 (manufactured by Mitsubishi Chemical Corporation), the column was washed with 100 ml of water and eluted with 50 ml of methanol. After concentrating the methanol eluate obtained here, high-performance liquid chromatography [M. Sano et al. Agric. Food Ch
em. , Vol. 47, 1906 (1999)].
【００２０】上記の分離条件は、 カラム：ＯＤＳ 内径２ｃｍ、長さ２５ｃｍ 流速：６．５ｍｌ／ｍｉｎ 移動相：アセトニトリルー水 （１５：８５） 検出波長：２８０ｎｍThe above separation conditions are as follows: Column: ODS inner diameter 2 cm, length 25 cm Flow rate: 6.5 ml / min Mobile phase: acetonitrile water (15:85) Detection wavelength: 280 nm
【００２１】このようにして、分離精製を行うと、保持
時間７２分に未反応のエピカテキン−３−Ｏ−ガレート
１３．４ｍｇを、保持時間１２０分にエピカテキン−３
−Ｏ−（４−Ｏ−メチル）ガレート１５．９ｍｇを得
た。When separation and purification are carried out in this manner, 13.4 mg of unreacted epicatechin-3-O-gallate is retained at a retention time of 72 minutes, and epicatechin-3 at a retention time of 120 minutes.
15.9 mg of -O- (4-O-methyl) gallate was obtained.
【００２２】その構造を以下の核磁気共鳴法及び旋光度
の測定により、それぞれの構造を確認した。The structure was confirmed by the following nuclear magnetic resonance method and measurement of optical rotation.
【００２３】[0023]
【化５】 Embedded image
【００２４】[0024]
【化６】 Embedded image
【００２５】エピカテキン−３−Ｏ−（４−Ｏ−メチ
ル）ガレートの旋光度、１Ｈ−ＮＭＲおよび１３Ｃ−Ｎ
ＭＲ ［α］Ｄ ２３ −１７３．８°（ｃ＝１．５９，ＭｅＯ
Ｈ）．１Ｈ−ＮＭＲ（ａｃｅｔｏｎｅ−ｄ６）：δ２．
９５（１Ｈ，ｄｄ，Ｊ＝１７．５，２．５ Ｈｚ，Ｈ−
４），３．０５（１Ｈ，ｄｄ，Ｊ＝１７．５，４．５Ｈ
ｚ，Ｈ−４），３．８３（３Ｈ，ｓ，ＯＭｅ），５．１
４（１Ｈ，ｂｒ ｓ，Ｈ−２），５．５７（１Ｈ，ｍ，
Ｈ−３），６．０４（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−
８），６．０６（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−６），
６．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ，Ｈ−５’），６．８
９（１Ｈ，ｄｄ，Ｊ＝８，２Ｈｚ，Ｈ−６’），７．０
０（２Ｈ，ｓ，Ｈ−２”，Ｈ−６”），７．０７（１
Ｈ，ｄ，Ｊ＝２ Ｈｚ，Ｈ−２’）．１３Ｃ−ＮＭＲ
（ａｃｅｔｏｎｅ−ｄ６）：δ２６．６（Ｃ−４），６
０．６（ＯＭｅ），６９．７（Ｃ−３），７８．０（Ｃ
−２），９５．９（Ｃ−８），９６．６（Ｃ−６），９
８．９（Ｃ−４ａ），１１０．０（Ｃ−２”，Ｃ−
６”），１１４．９（Ｃ−２’），１１５．７（Ｃ−
５’），１１９．１（Ｃ−６’），１２６．５（Ｃ−
１”），１３１．３（Ｃ−１’），１４０．５（Ｃ−４
），１４５．５／１４５．６（Ｃ−３’／Ｃ−
４’），１５１．１（Ｃ−３”，Ｃ−５”），１５７．
１（Ｃ−８ａ），１５７．５（Ｃ−６），１５７．８
（Ｃ−８），１６５．８（Ｃ−α）．Optical rotation, 1 H-NMR and 13 CN of epicatechin-3-O- (4-O-methyl) gallate
MR [α] D 23 -173.8 ° (c = 1.59, MeO
H). 1 H-NMR (acetone-d 6 ): δ2.
95 (1H, dd, J = 17.5, 2.5 Hz, H-
4), 3.05 (1H, dd, J = 17.5, 4.5H)
z, H-4), 3.83 (3H, s, OMe), 5.1
4 (1H, brs, H-2), 5.57 (1H, m,
H-3), 6.04 (1H, d, J = 2 Hz, H-
8), 6.06 (1H, d, J = 2 Hz, H-6),
6.77 (1H, d, J = 8 Hz, H-5 '), 6.8
9 (1H, dd, J = 8, 2 Hz, H-6 '), 7.0
0 (2H, s, H-2 ", H-6"), 7.07 (1
H, d, J = 2 Hz, H-2 ′). 13 C-NMR
(Acetone-d 6 ): δ 26.6 (C-4), 6
0.6 (OMe), 69.7 (C-3), 78.0 (C
-2), 95.9 (C-8), 96.6 (C-6), 9
8.9 (C-4a), 110.0 (C-2 ", C-
6 "), 114.9 (C-2 '), 115.7 (C-
5 '), 119.1 (C-6'), 126.5 (C-
1 "), 131.3 (C-1 '), 140.5 (C-4
), 145.5 / 145.6 (C-3 '/ C-
4 '), 151.1 (C-3 ", C-5"), 157.
1 (C-8a), 157.5 (C-6), 157.8
(C-8), 165.8 (C-α).
【００２６】（実施例３）カテキン−３−Ｏ−ガレート
４４．２ｍｇを２ｍｌのジメチルフォルムアミドに溶解
し、これに炭酸リチウム１８ｍｇ、ヨウ化メチル０．１
ｍｌを加え、反応容器内を窒素ガスで置換した後室温で
２０時間攪拌する。反応液は希塩酸にて酸性とし１０倍
量の水で希釈する。これを、ダイアイオンＨＰ−２０
（三菱化学社製）１２ｍｌを充填したカラムクロマトグ
ラフィーに付し、水１００ｍｌでカラムを洗浄した後、
メタノール５０ｍｌで溶出する。ここに得たメタノール
溶出液を濃縮後、高速液体クロマトグラフィー法［Ｍ．
Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．Ｆｏｏｄ Ｃｈｅ
ｍ．，ｖｏｌ．４７，１９０６（１９９９）］にて反応
生成物を分離精製する。Example 3 44.2 mg of catechin-3-O-gallate was dissolved in 2 ml of dimethylformamide, and 18 mg of lithium carbonate and 0.1 mg of methyl iodide were added thereto.
After the reaction vessel was replaced with nitrogen gas, the mixture was stirred at room temperature for 20 hours. The reaction solution is made acidic with diluted hydrochloric acid and diluted with 10 times the volume of water. This is called Diaion HP-20
After column chromatography packed with 12 ml (manufactured by Mitsubishi Chemical Corporation) and washing the column with 100 ml of water,
Elute with 50 ml of methanol. After concentrating the methanol eluate obtained here, high-performance liquid chromatography [M.
Sano et al. Agric. Food Che
m. , Vol. 47, 1906 (1999)].
【００２７】上記の分離条件は、 カラム：ＯＤＳ 内径２ｃｍ、長さ２５ｃｍ 流速：６．５ｍｌ／ｍｉｎ 移動相：アセトニトリルー水 （１７．５：８２．５） 検出波長：２８０ｎｍThe above separation conditions are as follows: Column: ODS inner diameter 2 cm, length 25 cm Flow rate: 6.5 ml / min Mobile phase: acetonitrile water (17.5: 82.5) Detection wavelength: 280 nm
【００２８】このようにして、分離精製を行うと、保持
時間４２分に未反応のカテキン−３−Ｏ−ガレート２
３．４ｍｇを、保持時間１２０分にカテキン−３−Ｏ−
（４−Ｏ−メチル）ガレート７．７ｍｇを得た。As described above, when separation and purification are performed, unreacted catechin-3-O-gallate 2 with a retention time of 42 minutes is obtained.
3.4 mg catechin-3-O- with a retention time of 120 minutes
7.7 mg of (4-O-methyl) gallate were obtained.
【００２９】[0029]
【化７】 Embedded image
【００３０】[0030]
【化８】 Embedded image
【００３１】カテキン３−Ｏ−（４−Ｏ−メチル）ガレ
ートの旋光度、１Ｈ−ＮＭＲおよび１３Ｃ−ＮＭＲ ［α］Ｄ ２３ −６２．７°（ｃ＝０．７７，ＭｅＯ
Ｈ）．１Ｈ−ＮＭＲ（ａｃｅｔｏｎｅ−ｄ６）：δ２．
７８（１Ｈ，ｄｄ，Ｊ＝１７，６ Ｈｚ，Ｈ−４），
２．９２（１Ｈ，ｄｄ，Ｊ＝１７，５Ｈｚ，Ｈ−４），
３．８５（３Ｈ，ｓ，ＯＭｅ），５．１４（１Ｈ，ｄ，
Ｊ＝６Ｈｚ，Ｈ−２），５．４０（１Ｈ，ｍ，Ｈ−
３），５．９９（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−８），
６．０７（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−６），６．８０
（２Ｈ，ｂｒ ｓ，Ｈ−２’，Ｈ−５’），６．９４
（１Ｈ，ｂｒｓ，Ｈ−６’），７．０２（２Ｈ，ｓ，Ｈ
−２”，Ｈ−６”）．１３Ｃ−ＮＭＲ（ａｃｅｔｏｎｅ
−ｄ６）：δ２４．４（Ｃ−４），６０．６（ＯＭ
ｅ），７０．９（Ｃ−３），７８．８（Ｃ−２），９
５．７（Ｃ−８），９６．５（Ｃ−６），９９．２（Ｃ
−４ａ），１１０．０（Ｃ−２”，Ｃ−６”），１１
４．４（Ｃ−２’），１１６．０（Ｃ−５’），１１
９．１（Ｃ−６’），１２６．４（Ｃ−１”），１３
１．３（Ｃ−１’），１４０．６（Ｃ−４”），１４
５．９（Ｃ−３’，Ｃ−４’），１５１．２（Ｃ−
３”，Ｃ−５”），１５６．３（Ｃ−８ａ），１５７．
２（Ｃ−６），１５８．１（Ｃ−８），１６５．８（Ｃ
−α）．Optical rotation of catechin 3-O- (4-O-methyl) gallate, 1 H-NMR and 13 C-NMR [α] D 23 -62.7 ° (c = 0.77, MeO
H). 1 H-NMR (acetone-d 6 ): δ2.
78 (1H, dd, J = 17, 6 Hz, H-4),
2.92 (1H, dd, J = 17, 5 Hz, H-4),
3.85 (3H, s, OMe), 5.14 (1H, d,
J = 6 Hz, H-2), 5.40 (1H, m, H-)
3), 5.99 (1H, d, J = 2 Hz, H-8),
6.07 (1H, d, J = 2 Hz, H-6), 6.80
(2H, brs, H-2 ', H-5'), 6.94.
(1H, brs, H-6 '), 7.02 (2H, s, H
-2 ", H-6"). 13 C-NMR (acetone
−d 6 ): δ 24.4 (C-4), 60.6 (OM
e), 70.9 (C-3), 78.8 (C-2), 9
5.7 (C-8), 96.5 (C-6), 99.2 (C
-4a), 110.0 (C-2 ", C-6"), 11
4.4 (C-2 '), 116.0 (C-5'), 11
9.1 (C-6 ′), 126.4 (C-1 ″), 13
1.3 (C-1 ′), 140.6 (C-4 ″), 14
5.9 (C-3 ', C-4'), 151.2 (C-
3 ", C-5"), 156.3 (C-8a), 157.
2 (C-6), 158.1 (C-8), 165.8 (C
-Α).
【００３２】（実施例４）ガロカテキン−３−Ｏ−ガレ
ート４５．８ｍｇを２ｍｌのジメチルフォルムアミドに
溶解し、これに炭酸リチウム１８ｍｇ、ヨウ化メチル
０．１ｍｌを加え、反応容器内を窒素ガスで置換した後
室温で２０時間攪拌する。反応液は希塩酸にて酸性とし
１０倍量の水で希釈する。これを、ダイアイオンＨＰ−
２０（三菱化学社製）１２ｍｌを充填したカラムクロマ
トグラフィーに付し、水１００ｍｌでカラムを洗浄した
後、メタノール５０ｍｌで溶出する。ここに得たメタノ
ール溶出液を濃縮後、高速液体クロマトグラフィー法
［Ｍ．Ｓａｎｏ等著、Ｊ．Ａｇｒｉｃ．ＦｏｏｄＣｈｅ
ｍ．，ｖｏｌ．４７，１９０６（１９９９）］にて反応
生成物を分離精製する。Example 4 45.8 mg of gallocatechin-3-O-gallate was dissolved in 2 ml of dimethylformamide, and 18 mg of lithium carbonate and 0.1 ml of methyl iodide were added thereto. After the replacement, the mixture is stirred at room temperature for 20 hours. The reaction solution is made acidic with diluted hydrochloric acid and diluted with 10 times the volume of water. This is called Diaion HP-
After column chromatography packed with 12 ml of 20 (manufactured by Mitsubishi Chemical Corporation), the column was washed with 100 ml of water and eluted with 50 ml of methanol. After concentrating the methanol eluate obtained here, high-performance liquid chromatography [M. Sano et al. Agric. FoodChe
m. , Vol. 47, 1906 (1999)].
【００３３】上記の分離条件は、 カラム：ＯＤＳ 内径２ｃｍ、長さ２５ｃｍ 流速：６．５ｍｌ／ｍｉｎ 移動相：アセトニトリルー水 （１５：８５） 検出波長：２８０ｎｍThe above separation conditions were as follows: column: ODS inner diameter 2 cm, length 25 cm Flow rate: 6.5 ml / min Mobile phase: acetonitrile water (15:85) Detection wavelength: 280 nm
【００３４】このようにして、分離精製を行うと、保持
時間３４分に未反応のガロカテキン−３−Ｏ−ガレート
１２．３ｍｇを、保持時間１２２分にガロカテキン−３
−Ｏ−（４−Ｏ−メチル）ガレート６．０ｍｇを得た。In this way, when separation and purification are performed, 12.3 mg of unreacted gallocatechin-3-O-gallate at a retention time of 34 minutes, and gallocatechin-3 at a retention time of 122 minutes.
6.0 mg of -O- (4-O-methyl) gallate was obtained.
【００３５】[0035]
【化９】 Embedded image
【００３６】[0036]
【化１０】 Embedded image
【００３７】ガロカテキン−３−Ｏ−（４−Ｏ−メチ
ル）ガレートの旋光度、１Ｈ−ＮＭＲおよび１３Ｃ−Ｎ
ＭＲ ［α］Ｄ ２３ −４３．３°（ｃ＝０．６０，ＭｅＯ
Ｈ）．１Ｈ−ＮＭＲ（ａｃｅｔｏｎｅ−ｄ６）：δ２．
７８（１Ｈ，ｄｄ，Ｊ＝１７，５．５Ｈｚ，Ｈ−４），
２．８４（１Ｈ，ｄｄ，Ｊ＝１７，５Ｈｚ，Ｈ−４），
３．８５（３Ｈ，ｓ，ＯＭｅ），５．１３（１Ｈ，ｄ，
Ｊ＝５．５Ｈｚ，Ｈ−２），５．４２（１Ｈ，ｍ，Ｈ−
３），５．９９（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−８），
６．０７（１Ｈ，ｄ，Ｊ＝２Ｈｚ，Ｈ−６），６．４９
（２Ｈ，ｂｒｓ，Ｈ−２’，Ｈ−６’），７．０２（２
Ｈ，ｓ，Ｈ−２”，Ｈ−６”）．１３Ｃ−ＮＭＲ（ａｃ
ｅｔｏｎｅ−ｄ６）：δ２３．７（Ｃ−４），６０．６
（ＯＭｅ），７０．７（Ｃ−３），７８．６（Ｃ−
２），９５．６（Ｃ−８），９６．４（Ｃ−６），９
９．１（Ｃ−４ａ），１０６．３（Ｃ−２’，Ｃ−
６’），１１０．０（Ｃ−２”，Ｃ−６”），１２６．
４（Ｃ−１”），１３０．８（Ｃ−１’），１３３．４
（Ｃ−４’），１４０．６（Ｃ−４”），１４６．６
（Ｃ−３’，Ｃ−５’），１５１．２（Ｃ−３”，Ｃ−
５”），１５６．２（Ｃ−８ａ），１５７．２（Ｃ−
６），１５８．０（Ｃ−８），１６５．９（Ｃ−α）．Optical rotation of gallocatechin-3-O- (4-O-methyl) gallate, 1 H-NMR and 13 CN
MR [α] D 23 -43.3 ° (c = 0.60, MeO
H). 1 H-NMR (acetone-d 6 ): δ2.
78 (1H, dd, J = 17, 5.5 Hz, H-4),
2.84 (1H, dd, J = 17, 5 Hz, H-4),
3.85 (3H, s, OMe), 5.13 (1H, d,
J = 5.5 Hz, H-2), 5.42 (1H, m, H-)
3), 5.99 (1H, d, J = 2 Hz, H-8),
6.07 (1H, d, J = 2 Hz, H-6), 6.49
(2H, brs, H-2 ', H-6'), 7.02 (2
H, s, H-2 ", H-6"). 13 C-NMR (ac
etone-d 6 ): δ 23.7 (C-4), 60.6
(OMe), 70.7 (C-3), 78.6 (C-
2), 95.6 (C-8), 96.4 (C-6), 9
9.1 (C-4a), 106.3 (C-2 ′, C-
6 ′), 110.0 (C-2 ″, C-6 ″), 126.
4 (C-1 ″), 130.8 (C-1 ′), 133.4
(C-4 '), 140.6 (C-4 "), 146.6
(C-3 ', C-5'), 151.2 (C-3 ", C-
5 "), 156.2 (C-8a), 157.2 (C-
6), 158.0 (C-8), 165.9 (C-α).
【００３８】[0038]
【本発明の効果】本発明によれば、カテキン類と炭酸リ
チウムを含むジメチルホルムアミド溶液にアルキルハラ
イドを添加し攪拌するというきわめて簡単な操作によっ
て、カテキン類の本来の優れた生物活性を保持しつつ、
かつ安定で抗アレルギー等の作用を発揮するカテキン誘
導体を提供することができる。According to the present invention, a very simple operation of adding an alkyl halide to a dimethylformamide solution containing catechins and lithium carbonate and stirring the mixture while maintaining the original excellent biological activity of the catechins. ,
It is possible to provide a catechin derivative which is stable and exhibits an action such as anti-allergy.
Claims (2)
のアルキル残基を示し、Ｒ８はＨまたはＯＨ、他は各々
独立にＨまたはβ−Ｄ−グルコース残基を示す）1. A catechin derivative represented by the general formula (1). Embedded image (Wherein at least one of R 1 to R 7 has 1 to 10 carbon atoms)
R 8 represents H or OH, and the others each independently represent H or β-D-glucose residue.
ハライドを炭酸リチウムの存在下で反応させることを特
徴とする請求項１記載の化合物の製造方法。2. The method according to claim 1, wherein catechin and an alkyl halide having 1 to 10 carbon atoms are reacted in the presence of lithium carbonate.
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