JPH0680706A

JPH0680706A - Cyclodextrin derivative

Info

Publication number: JPH0680706A
Application number: JP13051190A
Authority: JP
Inventors: Masanobu Yoshinaga; 雅信吉永
Original assignee: Toppan Printing Co Ltd
Current assignee: Toppan Inc
Priority date: 1990-05-21
Filing date: 1990-05-21
Publication date: 1994-03-22

Abstract

PURPOSE:To obtain a cyclodextrin derivative having improved solubility in water by introducing at least one sulfonic acid group into cyclodextrin. CONSTITUTION:For example, a pyridine solution of p-toluenesulfonyl chloride is added dropwise to a solution of beta-cyclodextrin in pyridine and the pyridine is distilled off in a vacuum. The residue is added to a large amount of acetone, and the formed precipitate is purified by recrystallization from water to obtain beta-cyclodextrin monotosylate. This compound is reacted with KI in dimethylformamide (DMF), and the DMF is distilled off in a vacuum to obtain beta-cyclodextrin monoiodide. This monoiodide is reacted with a reaction product of sodium hydroxymethanesulfonate with NaOH to obtain a cyclodextrin derivative having at least one sulfonic acid group.

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。TECHNICAL FIELD The present invention relates to a cyclodextrin derivative, and more specifically to a cyclodextrin derivative 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] In general, pharmaceuticals, chemicals such as agricultural chemicals, and the like are required to have water solubility in use. In recent years, as one of means for improving the water solubility, there has been proposed a method for improving the water solubility by including the above chemicals in cyclodextrin.

［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 that its water solubility is still insufficient in practical use. Therefore, in order to improve the solubility of cyclodextrin in water, methods such as methylating, hydroxyethylating, hydroxypropylating cyclodextrin, or synthesizing a crosslinked polymer using epichlorohydrin are performed. However, the full effect was not obtained yet.

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, it is an object of the present invention 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つのスルホ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] As a result of earnest research in view of the above problems, the present inventor achieved the above object of the present invention by providing a cyclodextrin derivative having at least one sulfonic acid group. I found that.

以下に本発明を更に詳細に説明する。 The present invention will be described in more detail below.

本発明はスルホン酸基（−ＳＯ_３Ｈ）をシクロデキストリン（以下、ＣＤと略記する）分子に確実に導入することにより水に対する溶解度を大幅に向上させるものであるが、この結果得られる本発明のＣＤ誘導体としては、具体的には、モノスルホン酸−β−ＣＤ、ヘプタスルホン酸−β− ＣＤ、ジスルホン酸β−ＣＤ、テトラデカスルホン酸β−ＣＤ、ヘンエイコサスルホン酸β−ＣＤ等が挙げられる。また、本発明に用いられるＣＤとしてはα−ＣＤ、β−ＣＤ、γ−ＣＤ等のいずれも用いることができる。The present invention significantly improves the solubility in water by accurately introducing a sulfonic acid group (—SO ₃ H) into a cyclodextrin (hereinafter abbreviated as CD) molecule. Specific examples of the CD derivative of are: monosulfonic acid-β-CD, heptasulfonic acid-β-CD, disulfonic acid β-CD, tetradecasulfonic acid β-CD, heneicosasulfonic acid β-CD. Etc. As the CD used in the present invention, any of α-CD, β-CD, γ-CD and the like can be used.

以下に、本発明の少なくとも１つのスルホン酸基を有するＣＤ誘導体の合成例をモノスルホン酸 β−ＣＤ、ジスルホン酸β−ＣＤ、ヘプタスルホン酸β−ＣＤ、テトラデカスルホン酸β−ＣＤ及びヘンエイコサスルホン酸β−ＣＤを例にとって示す。 The following are synthetic examples of the CD derivative having at least one sulfonic acid group of the present invention: monosulfonic acid β-CD, disulfonic acid β-CD, heptasulfonic acid β-CD, tetradecasulfonic acid β-CD and hen. An example is eicosasulfonic acid β-CD.

上記モノスルホン酸β−ＣＤ、ジスルホン酸β −ＣＤ、ヘプタスルホン酸β−ＣＤ、テトラデカスルホン酸β−ＣＤ及びヘンエイコサスルホン酸 β−ＣＤは具体的には下記のような方法で合成することができる。 The monosulfonic acid β-CD, disulfonic acid β-CD, heptasulfonic acid β-CD, tetradecasulfonic acid β-CD and heneicosasulfonic acid β-CD are specifically synthesized by the following method. be able to.

ｉ）モノスルホン酸β−ＣＤの合成例 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１昼夜、室温で撹拌し、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澱する。沈澱物を集め、水より再結晶を繰り返し精製する。（収率：２５％）得られたβ−ＣＤモノトシレートをＤＭＦ中でＫＩと７０〜８０℃で１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澱する。沈澱物はｎ−ブタノール／エタノール／水より再結晶し精製する。（収率：６０％）次に、ＤＭＦ中でヒドロキシメタンスルホン酸ナトリウム（ｘ＝１）とＮａＨを反応させ、そこに上記で得られたβ−ＣＤモノアイオダイドを加え、７０〜８０℃で１２時間撹拌し、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澱する。沈澱物をまとめて希塩酸にて処理することでβ−ＣＤモノスルホン酸を得た。i) Synthesis example of mono-sulfonic acid β-CD β-CD is dissolved in pyridine at room temperature, and paratoluenesulfonic acid chloride dissolved in pyridine is added dropwise at 20 ° C. After completion of the dropwise addition, the mixture is stirred at room temperature for one day and night. After completion of the reaction, pyridine is distilled off under reduced pressure at 40 ° C or lower, and the residue is added to a large amount of acetone for reprecipitation. The precipitate is collected and purified by repeating recrystallization from water. (Yield: 25%) The obtained β-CD monotosylate was reacted with KI in DMF at 70 to 80 ° C. for one day and night, and after the reaction was completed, DMF was distilled off under reduced pressure, and the residue was regenerated from a large amount of acetone. Settle. The precipitate is recrystallized from n-butanol / ethanol / water and purified. (Yield: 60%) Next, sodium hydroxymethanesulfonate (x = 1) was reacted with NaH in DMF, and the β-CD monoiodide obtained above was added thereto, and the temperature was adjusted to 70 to 80 ° C. After stirring for 12 hours, DMF is distilled off under reduced pressure after the reaction is completed, and the residue is reprecipitated from a large amount of acetone. The precipitates were combined and treated with dilute hydrochloric acid to obtain β-CD monosulfonic acid.

（収率：４０％） ii)ヘプタスルホン酸β−ＣＤの合成例ＤＭＦ中に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時間撹拌する。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澱する。そして塩基で中和後氷冷水に加え、濾過し、沈澱物を氷冷水で繰り返し洗浄し減圧乾燥し、β−ＣＤヘプタブロマイドを得る。（収率：８０％）次にＤＭＦ中でヒドロキシメタンスルホン酸ナトリウム（ｎ＝１）とＮａＨを反応させ、これに上記で得られたβ−ＣＤヘプタブロマイドを加え７０〜８０℃で２４時間撹拌し、終了後ＤＭＦを減圧下で留去し、残渣を大量のアセトン中より再沈澱させる。沈澱物はカラム分離により精製し、続いて塩酸にて処理して、β−ＣＤヘプタスルホン酸を得る。（収率：２０％） iii)ジスルホン酸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℃にて滴下する。滴下終了後２０℃以下にて１昼夜撹拌、反応終了後ピリジンを４０℃以下にて減圧留去し残渣を大量のアセトンより再沈澱を行なった。沈澱物を集め水より再結晶を繰り返し精製する。（収率：１５％）… 得られた化合物をＤＭＦ中でＫＩと７０〜８０℃で１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澱する。沈澱物はｎ−ブタノール／エタノール／水より再結晶し、精製する。（収率：５５％）… 次にＤＭＦ中でヒドロキシメタンスルホン酸ナトリウム（ｘ＝１）とＮａＨを反応させ、そこに上記で得られたを室温で加え、７０〜８０℃で２４時間撹拌し、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澱する。沈澱物をまとめて希塩酸にて処理することでジスルホン酸β−ＣＤを得た。（収率：３０％） iv)テトラデカスルホン酸β−ＣＤの合成 β−ＣＤとイミダゾールを室温下ＤＭＦに溶解し、これにＤＭＦに溶解したｔ−ブチルジメチルシリルクロライドを滴下する。滴下終了後６時間室温にて撹拌、反応終了後ＤＭＦを減圧下で留去、残渣をシリカゲルカラムクロマトグラフィーにより分離した。（展開溶媒：クロロホルム−エタノール）得られた化合物をさらにエタノールより再結晶することでを精製した。(Yield: 40%) ii) Synthesis example of heptasulfonic acid β-CD Dissolve β-CD in DMF, add methanesulfonyl bromide, and stir at 60 to 70 ° C for 24 hours after addition. After completion of the reaction, 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 is added to ice-cold water, filtered, and the precipitate is repeatedly washed with ice-cold water and dried under reduced pressure to obtain β-CD heptabromide. (Yield: 80%) Next, sodium hydroxymethanesulfonate (n = 1) was reacted with NaH in DMF, and the β-CD heptabromide obtained above was added thereto, and the mixture was heated at 70 to 80 ° C. for 24 hours. After stirring and after completion, DMF is distilled off under reduced pressure, and the residue is reprecipitated from a large amount of acetone. The precipitate is purified by column separation and subsequently treated with hydrochloric acid to obtain β-CD heptasulfonic acid. (Yield: 20%) iii) Synthesis of disulfonic acid β-CD β-CD was dissolved in pyridine at room temperature, and diphenylmethane p, p′-disulfonyl chloride dissolved in pyridine was added dropwise at 5 ° C. . After completion of dropping, the mixture was stirred at 20 ° C. or lower for one day and night, after completion of the reaction, pyridine was distilled off under reduced pressure at 40 ° C. or lower, and the residue was reprecipitated from a large amount of acetone. The precipitate is collected and repeatedly recrystallized from water for purification. (Yield: 15%) ... The obtained compound is reacted with KI in DMF at 70-80 ° C. for one day and 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 recrystallized from n-butanol / ethanol / water and purified. (Yield: 55%) Next, sodium hydroxymethanesulfonate (x = 1) is reacted with NaH in DMF, the above-obtained product is added thereto at room temperature, and the mixture is stirred at 70 to 80 ° C. for 24 hours. After completion of the reaction, DMF is distilled off under reduced pressure and the residue is reprecipitated from a large amount of acetone. The precipitates were combined and treated with dilute hydrochloric acid to obtain disulfonic acid β-CD. (Yield: 30%) iv) Synthesis of β-CD tetradecasulfonic acid β-CD and imidazole are dissolved in DMF at room temperature, and t-butyldimethylsilyl chloride dissolved in DMF is added dropwise thereto. After completion of dropping, the mixture was stirred for 6 hours at room temperature, after completion of reaction, DMF was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography. (Developing solvent: chloroform-ethanol) The obtained compound was purified by further recrystallization from ethanol.

▲Ａ▼法：次にをＤＭＦ中に溶解し、室温下窒素雰囲気でＮａＨと反応させる。そしてＤＭＦに溶解したクロルメタンスルホン酸ナトリウム（ｘ＝１）をゆくっり滴下し、滴下終了後６０〜７０℃ で１２時間反応させた。反応終了後ＤＭＦを減圧下で留去、残渣を大量のエチルエーテルより再沈澱して沈澱物をまとめて希塩酸にて処理することでを得た。（収率：４５％） ▲Ｂ▼法：次にをＤＭＦ中に溶解し、室温下窒素雰囲気でＮａＨと反応させる。そしてＤＭＦを溶解した１，３−プロパンサルトン（ｙ＝１）をゆっくり滴下し、滴下終了後室温で２４時間反応させた。反応終了後ＤＭＦを減圧下で留去、残渣を大量のエチルエーテルより再沈澱し、沈澱物をまとめて希塩酸にて処理することでを得た。（収率：７０％），をそれぞれＴＨＦに溶解し、室温下ＴＨＦに溶解したテトラブチルアンモニウムフルオライドを滴下する。滴下終了後、還流下５時間反応させ、その後減圧下ＴＨＦを留去する。残渣を少量のＤＭＦに溶解しアセトンより再沈澱を繰り返し行なうことで精製し、それぞれ，を得た（の収率７５％，の収率７０％）。Method A: Next, is dissolved in DMF and reacted with NaH in a nitrogen atmosphere at room temperature. Then, sodium chloromethanesulfonate (x = 1) dissolved in DMF was slowly added dropwise, and after completion of the addition, reaction was carried out at 60 to 70 ° C. for 12 hours. After completion of the reaction, DMF was distilled off under reduced pressure, the residue was reprecipitated from a large amount of ethyl ether, and the precipitates were combined and treated with dilute hydrochloric acid to obtain the product. (Yield: 45%) Method B: Next, is dissolved in DMF and reacted with NaH in a nitrogen atmosphere at room temperature. Then, DMF-dissolved 1,3-propanesartone (y = 1) was slowly added dropwise, and after completion of the addition, reaction was carried out at room temperature for 24 hours. After completion of the reaction, DMF was distilled off under reduced pressure, the residue was reprecipitated from a large amount of ethyl ether, and the precipitate was collected and treated with dilute hydrochloric acid to obtain the product. (Yield: 70%) are each dissolved in THF, and tetrabutylammonium fluoride dissolved in TH F is added dropwise at room temperature. After completion of the dropping, the mixture is reacted under reflux for 5 hours, and then THF is distilled off under reduced pressure. The residue was dissolved in a small amount of DMF and purified by repeating re-precipitation from acetone to obtain (, yield: 75%, yield: 70%).

ｖ）ヘンエイコサスルホン酸β−ＣＤの合成 β−ＣＤをＤＭＦ中に溶解し、５℃以下窒素雰囲気でＮａＨと反応させる。そしてＤＭＦに溶解した１，３−プロパンサルトン（ｙ＝１）をゆっくり滴下し、滴下終了後室温で６０時間反応させた。反応終了後ＤＭＦを減圧下で留去、残渣を大量のジクロメタンより再沈澱を行なった。沈澱物をまとめて希塩酸にて処理することでヘンエイコサスルホン酸β−ＣＤを得た。（収率：２５％）それぞれの目的物の確認は、ＮＭＲスペクトル、マススペクトル、元素分析などの方法を用いて行なう。v) Synthesis of heneicosasulfonic acid β-CD β-CD is dissolved in DMF and reacted with NaH in a nitrogen atmosphere at 5 ° C or lower. Then, 1,3-propanesartone (y = 1) dissolved in DMF was slowly added dropwise, and after completion of the addition, reaction was carried out at room temperature for 60 hours. After completion of the reaction, DMF was distilled off under reduced pressure, and the residue was reprecipitated from a large amount of dichloromethane. The precipitates were combined and treated with dilute hydrochloric acid to obtain heneicosasulfonic acid β-CD. (Yield: 25%) Confirmation of each target product is performed by using methods such as NMR spectrum, mass spectrum, and elemental analysis.

その他のＣＤ誘導体についても上記方法に準じて同様に合成することができる。 Other CD derivatives can be similarly synthesized according to the above method.

上記の如く得られるＣＤ誘導体の水に対する溶解度を調べた結果を以下に示す。 The results of examining the solubility of the CD derivative obtained as described above in water are shown below.

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ができる。 The highly water-soluble CD derivative of the present invention can be used, for example, in medicines such as medicines and agricultural chemicals, fragrances, cosmetics, detergents, paints, dyes, and food additives for foods.

［発明の効果］以上詳細に述べたように、本発明によりスルホン酸基をＣＤに確実に導入することにより、ＣＤの水に対する溶解度を大幅に向上させることができ、この結果水溶性の高いＣＤ包接化合物を得ることができる。[Effects of the Invention] As described in detail above, by reliably introducing a sulfonic acid group into CD according to the present invention, the solubility of CD in water can be significantly improved, and as a result, the water solubility of CD can be improved. It is possible to obtain a high CD inclusion compound.

Claims

[Claims]

1. A cyclodextrin derivative having at least one sulfonic acid group.