JPH0481402A - Cyclodextrin derivative - Google Patents
Cyclodextrin derivativeInfo
- Publication number
- JPH0481402A JPH0481402A JP19546890A JP19546890A JPH0481402A JP H0481402 A JPH0481402 A JP H0481402A JP 19546890 A JP19546890 A JP 19546890A JP 19546890 A JP19546890 A JP 19546890A JP H0481402 A JPH0481402 A JP H0481402A
- Authority
- JP
- Japan
- Prior art keywords
- water
- cyclodextrin
- derivative
- under reduced
- reduced pressure
- 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
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明はシクロデキストリン誘導体に関し、更に詳しく
は高い水溶性を有するシクロデキストリン誘導体に関す
る。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to cyclodextrin derivatives, and more particularly to cyclodextrin derivatives having high water solubility.
［従来の技術］
一般に医薬、農薬等の薬品類等は用途上、水溶性を有す
ることが求められる。近年、これらの水溶性を向上させ
る手段の一つとして、上記薬品類等をシクロデキストリ
ンに包接させることによって水溶性を向上させる方法が
提案されている。[Prior Art] Generally, chemicals such as medicines and agricultural chemicals are required to be water-soluble due to their usage. In recent years, as one means for improving the water solubility of these substances, a method has been proposed in which the above-mentioned chemicals and the like are included in cyclodextrin to improve the water solubility.
［発明が解決しようとする課題］
しかしながら、このようなシクロデキストリン包接化合
物においても、シクロデキストリン自体の水への溶解度
に限度があるため、その水溶性は実用上未だ不十分であ
った。このため、シクロデキストリンの水に対する溶解
度を向上させるため、シクロデキストリンをメチル化、
ヒドロキシエチル化、ヒドロキシプロピル化するか、あ
るいはエピクロルヒドリンを用いて架橋させたポリマー
を合成する等の方法が行なわれているが、未だ十分な効
果は得られていなかった。[Problems to be Solved by the Invention] However, even in such a cyclodextrin clathrate compound, the solubility of cyclodextrin itself in water is limited, so its water solubility is still insufficient for practical use. Therefore, in order to improve the solubility of cyclodextrin in water, cyclodextrin is methylated and
Methods such as hydroxyethylation, hydroxypropylation, or synthesis of crosslinked polymers using epichlorohydrin have been used, but sufficient effects have not yet been obtained.
従って、本発明の目的は、水に対して極めて高い溶解性
を有するシクロデキストリン誘導体を提供することにあ
る。Therefore, an object of the present invention is to provide a cyclodextrin derivative having extremely high solubility in water.
［課題を解決するための手段］
本発明者は前記課題に鑑みて鋭意研究の結果、本発明の
上記目的は、少なくとも１つのリン酸基を有するシクロ
デキストリン誘導体を提供することにより達成されるこ
とを見出した。[Means for Solving the Problems] In view of the above-mentioned problems, the present inventors have conducted extensive research and found that the above-mentioned objects of the present invention can be achieved by providing a cyclodextrin derivative having at least one phosphate group. I found out.
以下に本発明を更に詳細に説明する。The present invention will be explained in more detail below.
本発明の少なくとも１つのリン酸基を有するシクロデキ
ストリン（以下ＣＤと称す）誘導体においてリン酸基と
しては好ましくは−Ｐ（ＯＨ）２であり、このような化
合物としては具体的には、例えばモノリン酸β−ＣＤ、
シリン酸β−ＣＤ、ヘプタリン酸β−ＣＤ等が挙げられ
る。これらＣＤ誘導体の合成反応について以下に示す。In the cyclodextrin (hereinafter referred to as CD) derivative having at least one phosphate group of the present invention, the phosphate group is preferably -P(OH)2, and specific examples of such compounds include, for example, monophosphate acid β-CD,
Examples include β-CD syric acid, β-CD heptalate, and the like. Synthetic reactions for these CD derivatives are shown below.
以下余白
■
モノリン酸β−ＣＤ；
■
シリン酸β−ＣＤ （４）；
■
ヘプタリン酸β−ＣＤ；
また、上記反応についての具体的合成例について以下に
示す。In the following margins: (1) monophosphate β-CD; (2) syric acid β-CD (4); (2) heptalic acid β-CD; Further, specific synthesis examples for the above reactions are shown below.
■モノリン酸β−ＣＤの合成
β−ＣＤを室温下ピリジンに溶解し、これにピノジンに
溶解したパラトルエンスルホン酸クロライドを２０℃に
て滴下する。滴下終了後−昼夜、室温で攪拌し、反応終
了後、ピリジンを４０℃以下で減圧留去し、残渣を大量
のアセトン中に加え再沈号する。沈殿物を集め、水より
再結晶を繰り返し精製し、β−ＣＤモノトシレート（１
）を得る。(2) Synthesis of monophosphoric acid β-CD β-CD is dissolved in pyridine at room temperature, and paratoluenesulfonic acid chloride dissolved in pinodine is added dropwise thereto at 20°C. After completion of the dropwise addition - Stirring is carried out day and night at room temperature. After completion of the reaction, pyridine is distilled off under reduced pressure at 40 DEG C. or below, and the residue is added to a large amount of acetone for reprecipitation. The precipitate was collected and purified by repeated recrystallization from water to obtain β-CD monotosylate (1
).
（収率：２５％）
得られたβ−ＣＤモノトシレートをＤＭＦ中で（Ｉと７
０〜８０℃で一昼夜反応させ、反応終了後）ＭＦを減圧
下で留去し、残渣を大量のアセトンより再沈殿する。沈
殿物はｎ−ブタノール／エタノール／水より再結晶し、
精製し化合物（２）を得る。（収率：６０％）
次に得られたβ−ＣＤモノアイオダイドをつＭＦに溶解
し、トリエチルホスファイトと９０〜００℃で２４時間
反応させる。反応終了後、トリエチルホスファイト、Ｄ
ＭＦを減圧下で留去し、残渣を大量のアセトンより再沈
殿を行ない、沈殿物は集めてよく水洗し得られた結晶を
減圧乾燥する。(Yield: 25%) The obtained β-CD monotosylate was dissolved in DMF (I and 7
The reaction is carried out at 0 to 80° C. for one day, and after the reaction is completed, MF is distilled off under reduced pressure, and the residue is reprecipitated from a large amount of acetone. The precipitate was recrystallized from n-butanol/ethanol/water,
Purification is performed to obtain compound (2). (Yield: 60%) Next, the obtained β-CD monoiodide is dissolved in MF and reacted with triethyl phosphite at 90 to 00°C for 24 hours. After the reaction, triethyl phosphite, D
MF is distilled off under reduced pressure, the residue is reprecipitated from a large amount of acetone, the precipitate is collected and thoroughly washed with water, and the resulting crystals are dried under reduced pressure.
その結晶を少量のＤＭＦに溶解し、ブロモトリメチルシ
ラン（ＢＴＭＳ）を加えて３０〜４０°Ｃで１２時間反
応させる。反応終了後、ＢＴＭＳ、ＤＭＦを減圧下で留
去し、残渣を大量のジエチルエーテルより再沈殿を行な
い、沈殿物を集めてクロロホルム／エタノール系より再
結晶を行ない、精製し、モノリン酸β−ＣＤ（モノ−６
−ジヒドロキシホスフォニル−６−デオキシβ−ＣＤ）
を得る。The crystals are dissolved in a small amount of DMF, bromotrimethylsilane (BTMS) is added, and the mixture is reacted at 30-40°C for 12 hours. After the reaction, BTMS and DMF were distilled off under reduced pressure, the residue was reprecipitated from a large amount of diethyl ether, the precipitate was collected and recrystallized from a chloroform/ethanol system, and purified to obtain monophosphoric acid β-CD. (Mono-6
-dihydroxyphosphonyl-6-deoxyβ-CD)
get.
（収率：３５％）
■シリン酸β−ＣＤの合成
β−ＣＤを室温下ピリジンに溶解し、これにピリジンに
溶解したジフェニルメタンｐ、ｐ −ジスルホニルクロ
ライドを５°Ｃにて滴下する。滴下終了後２０’Ｃ以下
にて一昼夜攪拌し、反応終了後ピリジンを４０°Ｃ以下
にて減圧留去し、残渣を大量のアセトンより再沈殿を行
なう。沈殿物を集めて水より再結晶を繰り返し精製しく
１）を得る。（収率：１５％）
得られた化合物（１）をＤＭＦ中でＫＩと７０〜８０°
Ｃで一昼夜反応させ、反応終了後ＤＭＦを減圧下で留去
し、残渣を大量のアセトンより再沈殿する。沈殿物を集
めてｎ−ブタノール／エタノール／水より再結晶し精製
し化合物（２）を得る。(Yield: 35%) (1) Synthesis of β-CD syric acid β-CD is dissolved in pyridine at room temperature, and diphenylmethane p,p-disulfonyl chloride dissolved in pyridine is added dropwise thereto at 5°C. After completion of the dropwise addition, the mixture was stirred for a day and night at a temperature below 20°C, and after completion of the reaction, pyridine was distilled off under reduced pressure at a temperature below 40°C, and the residue was reprecipitated from a large amount of acetone. The precipitate is collected and purified by repeated recrystallization from water to obtain 1). (Yield: 15%) The obtained compound (1) was mixed with KI at 70-80° in DMF.
After the reaction is completed, DMF is distilled off under reduced pressure, and the residue is reprecipitated from a large amount of acetone. The precipitate is collected and purified by recrystallization from n-butanol/ethanol/water to obtain compound (2).
（収率：５５％）
次に得られた化合物（２）をＤＭＦに溶解し、トリエチ
ルホスファイトと９０〜１００°Ｃで２４時間反応させ
る。反応終了後トリエチルホスファイト。(Yield: 55%) Next, the obtained compound (2) is dissolved in DMF and reacted with triethyl phosphite at 90 to 100°C for 24 hours. Triethyl phosphite after the reaction is completed.
ＤＭＦを減圧下で留去し、残渣を大量のアセトンより再
沈殿を行ない、沈殿物は集めてよく水洗し得られた結晶
を減圧乾燥し化合物（３）を得る。DMF is distilled off under reduced pressure, the residue is reprecipitated from a large amount of acetone, the precipitate is collected and thoroughly washed with water, and the resulting crystals are dried under reduced pressure to obtain compound (3).
さらに、得られた化合物（３）を少量のＤＭＦに溶解し
、ＢＴＭＳを加えて３０〜４０°Ｃで１２時間反応させ
る。反応終了後、ＢＴＭＳ、ＤＭＦを減圧下で留去した
後、残渣を大量のジエチルエーテルより再沈殿を行ない
、沈殿物は集めてクロロホルム／エタノール系より再結
晶を行ない精製してシリン酸β−ＣＤ （４）を得る。Furthermore, the obtained compound (3) is dissolved in a small amount of DMF, BTMS is added, and the mixture is reacted at 30 to 40°C for 12 hours. After the reaction, BTMS and DMF were distilled off under reduced pressure, and the residue was reprecipitated from a large amount of diethyl ether. The precipitate was collected and purified by recrystallization from a chloroform/ethanol system to obtain β-CD syric acid. (4) is obtained.
（収率：２５％）■へブタリン酸β−ＣＤの合成
りＭＦ中に室温でβ−ＣＤを溶解し、メタンスルホニル
ブロマイドを加え、添加後６０〜７０℃で２４時間攪拌
する。反応終了後、ＤＭＦを減圧下で留去し残渣を大量
のメタノールより再沈殿する。次いで塩基で中和後、氷
冷水に加え濾過した後、沈殿物を氷冷水で洗浄し減圧乾
燥しβ−ＣＤへブタブロマイドを得た。（収率：８０％
）
次にβ−ＣＤへブタブロマイドをＤＭＦに溶解し、トリ
エチルホスファイトと９０〜１００°Ｃで６００時間反
応せる。反応終了後トリエチルホスファイト、ＤＭＦを
減圧下で留去し、残渣を大量のアセトンより再沈殿を行
ない、沈殿物は集めてよく水洗し、得られた結晶を減圧
乾燥した。(Yield: 25%) ① Synthesis of hebutyric acid β-CD β-CD is dissolved in MF at room temperature, methanesulfonyl bromide is added, and after the addition, the mixture is stirred at 60 to 70°C for 24 hours. After the reaction is completed, DMF is distilled off under reduced pressure and the residue is reprecipitated from a large amount of methanol. After neutralization with a base, the mixture was added to ice-cold water and filtered, and the precipitate was washed with ice-cold water and dried under reduced pressure to obtain β-CD butabromide. (Yield: 80%
) Next, β-CD hebutabromide is dissolved in DMF and reacted with triethyl phosphite at 90-100°C for 600 hours. After the reaction was completed, triethyl phosphite and DMF were distilled off under reduced pressure, and the residue was reprecipitated from a large amount of acetone. The precipitate was collected and thoroughly washed with water, and the obtained crystals were dried under reduced pressure.
さらにその結晶を少量のＤＭＦに溶解し、ブロモトリメ
チルシラン（ＢＴＭＳ）を加えて３０〜４０℃で３００
時間反応せる。反応終了後、ＢＴＭＳ。Further, the crystals were dissolved in a small amount of DMF, bromotrimethylsilane (BTMS) was added, and the crystals were heated at 30 to 40°C.
Time reaction. After the reaction is completed, BTMS.
ＤＭＦを減圧下で留去、残渣を大量のＴＨＦより再沈殿
を行ない、沈殿物は集めてクロロホルム／エタノール系
より再結晶を行ない精製して、ヘプタリン酸β−ＣＤを
得る。（収率：１０％）なお、目的物の確認、ＮＭＲス
ペクトル、マススペクトル、元素分析なとの方法を用い
て行なった。DMF is distilled off under reduced pressure, the residue is reprecipitated from a large amount of THF, and the precipitate is collected and purified by recrystallization from a chloroform/ethanol system to obtain heptalic acid β-CD. (Yield: 10%) The target product was confirmed using methods such as NMR spectrum, mass spectrum, and elemental analysis.
前記の如く得られるシクロデキストリン誘導体の水に対
する溶解度を調べた。結果を以下に記す。The solubility of the cyclodextrin derivative obtained as described above in water was investigated. The results are described below.
水に対する溶解度（ｇ７１００ｍり水）本発明において
はＣＤとしてα型ＣＤ、β型ＣＤ４及びγ型ＣＤのいず
れも用いることができる。Solubility in water (g 7100 ml of water) In the present invention, any of α-type CD, β-type CD4, and γ-type CD can be used as CD.
本発明の高い水溶性を有するＣＤ誘導体は、例えば医薬
、農薬等の薬品、芳香剤、化粧品、洗剤、塗料、染料、
食料品の食品添加物等に用いることかできる。The highly water-soluble CD derivative of the present invention can be used, for example, in pharmaceuticals, chemicals such as agricultural chemicals, fragrances, cosmetics, detergents, paints, dyes, etc.
It can be used as a food additive for foodstuffs.
［発明の効果］
以上詳細に述べたように、本発明によりリン酸基をシク
ロデキストリンに確実に導入することで水に対する溶解
度を大幅に向上させることか出来、この結果水溶性の高
いシクロデキストリン包接化合物を得ることができる。[Effects of the Invention] As described in detail above, the present invention makes it possible to significantly improve the solubility in water by reliably introducing a phosphoric acid group into cyclodextrin, and as a result, highly water-soluble cyclodextrin capsules can be obtained. A junction compound can be obtained.
Claims (1)
誘導体。A cyclodextrin derivative having at least one phosphate group.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19546890A JPH0481402A (en) | 1990-07-24 | 1990-07-24 | Cyclodextrin derivative |
| PCT/JP1991/000666 WO1991018022A1 (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivative |
| EP95119260A EP0710673A3 (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivatives |
| DE69127256T DE69127256T2 (en) | 1990-05-21 | 1991-05-20 | CYCLODEXTRIN DERIVATIVE |
| CA002063454A CA2063454A1 (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivatives |
| US07/776,296 US5241059A (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivatives |
| KR1019920700037A KR927003645A (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivatives |
| EP91909367A EP0485614B1 (en) | 1990-05-21 | 1991-05-20 | Cyclodextrin derivative |
| EP95119259A EP0710672A3 (en) | 1990-05-21 | 1991-05-25 | Cyclodextrin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19546890A JPH0481402A (en) | 1990-07-24 | 1990-07-24 | Cyclodextrin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0481402A true JPH0481402A (en) | 1992-03-16 |
Family
ID=16341584
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19546890A Pending JPH0481402A (en) | 1990-05-21 | 1990-07-24 | Cyclodextrin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0481402A (en) |
-
1990
- 1990-07-24 JP JP19546890A patent/JPH0481402A/en active Pending
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