JP4026875B2 - Method for producing cyclodextrin derivative - Google Patents

Description

【０００８】
（式中、Ｒは無置換若しくは置換スルホニル基、または無置換若しくは置換アシル基である。）
以下、本発明を詳細に説明する。
【０００９】
【発明の実施の態様】
本発明において、シクロデキストリンとは、無置換及び置換α−シクロデキストリン(n=6) 、無置換及び置換β−シクロデキストリン(n=7) 、無置換及び置換γ−シクロデキストリン(n=8) をいう。また置換シクロデキストリンとは、シクロデキストリンを構成するＤ(+)-グルコピラノース単位の２位水酸基以外の位置に置換基が存在するシクロデキストリンをいう。例えば、シクロデキストリンの３位及び／または６位の水酸基が修飾されたシクロデキストリンを挙げることができる。また、本発明の製造方法によれば、原料となるシクロデキストリンを構成する少なくとも１つのＤ(+)-グルコピラノース単位の２位水酸基をスルホニル化またはアシル化したシクロデキストリン誘導体を得ることができる。スルホニル基またはアシル基の導入個数は反応条件をコントロールすることにより適宜調整でき、条件により、以下の式（２）で示される１つのＤ(+)-グルコピラノース単位の２位水酸基をスルホニル化またはアシル化したシクロデキストリン誘導体を得ることができる。
【００１０】
【化４】

【００１１】
（式中、Ｒは無置換若しくは置換スルホニル基、または無置換若しくは置換アシル基である。）
１つのＤ(+)-グルコピラノース単位の２位水酸基が置換されたシクロデキストリン誘導体の製造方法の反応スキームを以下に示す。
【００１２】
【化５】

【００１３】
本発明の製造方法において、上記シクロデキストリンと式（１）で示されるイミダゾール誘導体とを反応させる。式（１）中のＲは、無置換若しくは置換スルホニル基、または無置換若しくは置換アシル基である。ここで、スルホニル基、及びアシル基の置換基Ｘとしては、低級アルキル基（例えば、メチル、エチル、プロピル、ブチル等）、無置換芳香族基（例えば、フェニル、ナフチル）及び置換基として低級アルキル基（例えば、メチル、エチル、プロピル、ブチル等）やニトロ基を有する芳香族基を挙げることができる。
【００１４】
式（１）で示されるイミダゾール誘導体の具体例を以下に示す。
スルホニルイミダゾール：メタンスルホニルイミダゾール、エタンスルホニルイミダゾール、プロパンスルホニルイミダゾール、ブタンスルホニルイミダゾール等の直鎖状、分岐鎖状もしくは環状の脂肪基族スルホニルイミダゾール、及びｐ−トルエンスルホニルイミダゾール、ｔ−ブチルベンゼンスルホニルイミダゾール、ニトロベンゼンスルホニルイミダゾール、ナフチルスルホニルイミダゾール等の芳香族スルホニルイミダゾールであり、これらは置換基を有するものであってもよい。
アシルイミダゾール：ホルミルイミダゾール、アセチルイミダゾール、プロピオニルイミダゾール、ブチリルミダゾール、バレリルイミダゾール、ピバイロイルイミダゾール等の直鎖状、分岐鎖状もしくは環状の脂肪族カルボニルイミダゾール、およびベンゾイルイミダゾール等の芳香族カルボニルイミダゾールであってもよい。
【００１５】
イミダゾール誘導体は、市販されているもがあり、また、市販品がない場合でも、以下の方法により容易に製造することができる。
市販のイミダゾールを、60％NaH を含むN,N-ジメチルホルムアミド(15ml)に、氷冷下で攪拌しながら徐々に加え、加え終わってから更に20分攪拌する。その後、スルホニルクロリドやアシルクロリド等のクロリド類を徐々に加え30分攪拌する。反応液を水に加え、ベンゼンで抽出し、更に水層よりベンゼンで２回抽出する。抽出液をあわせ、水で洗浄した後、無水硫酸マグネシウムで脱水し、減圧濃縮する。残渣より置換イミダゾール（イミダゾール誘導体）を得る。
【００１６】
本発明の反応は、触媒として、モレキュラーシーブスの存在下で行う。モレキュラーシーブスとしては、例えば、MS3A、MS4A、MS5A、MS13X 等を挙げることができる。また、その形状は、粉末或いはペレットであってもよい。また、本反応におけるモレキュラーシーブスの役割は、イミダゾール試薬とシクロデキストリンとの反応を活性化するための触媒であり、一般に用いられるところの脱水作用の役割をしているのではない。したがって、使用するモレキュラーシーブスは、脱水作用に対して活性済みのもの、脱水作用に対して不活性のもの、水分を多量に含むもの、いずれでもよい。即ち、モレキュラーシーブスは、活性化モレキュラーシーブスまたは不活性化モレキュラーシーブスのいずれでもよい。
【００１７】
本発明の反応は、溶媒の存在下で行うことが好ましく、溶媒は、反応に関与しないものならばいずれも使用できる。但し、反応物の溶解性が良好であるという観点から、無水または含水の塩基性有機溶媒であることが適当である。塩基性有機溶媒の例としては、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、1-メイチル-2- ピロリドン等のアミド系極性溶媒、及びピリジン等を挙げることができる。なお、本反応は無水条件を必要としないので、溶媒は水分を含んでいてもよい。同様に、シクロデキストリンは乾燥したものでも、水分を含んだものいずれでもよい。
本発明の反応は、通常、室温下で行うことができ、また、反応収率や置換基の導入個数等を考慮して、昇温下または冷却下で行うこともできる。また、反応時間は、反応収率等を考慮して適宜決定することができ、例えば、１０〜２００時間の範囲であることが適当である。
【００１８】
イミダゾール誘導体の添加量は、目的とするシクロデキストリンに対する置換基の導入個数、反応温度や反応時間、用いる溶媒とシクロデキストリン及びモレキュラーシーブスの重量比率などの反応条件によって異なるが、シクロデキストリン１モルに対して、１〜１０モルの範囲で反応系に添加することが適当である。好ましくは、シクロデキストリン１モルに対して、導入する置換基のモル数と等量のイミダゾール誘導体を用いることが好ましい。
反応系において、シクロデキストリンは溶媒に完全に溶解していることが望ましく、また溶解しているシクロデキストリン濃度が高い程、反応を効率よく行うことができる。従って、用いる溶媒の量は、シクロデキストリン１重量部に対して、５〜１００重量部の範囲とすることが適当である。好ましくは、用いるシクロデキストリン及び溶媒の種類、反応温度において、シクロデキストリンの飽和濃度となる量であることが望ましい。
また、用いるモレキュラーシーブス量が多ければ多い程、高い効率で置換基を導入でき、シクロデキストリン誘導体の収率を向上し、且つ反応時間を短縮できる。従って、モレキュラーシーブスの量は、反応に用いる装置の攪拌システムに支障が起こらない範囲で無制限に用いることができる。但し、実用的には、溶媒１重量部に対して０．０１〜０．２重量部の範囲であることが適当である。また、反応液にモレキュラーシーブスを添加する以外に、モレキュラーシーブスを充填したカラムに反応液を添加してカラム中で反応させることもできる。
本発明の反応により、スルホニル化、またはアシル化は、シクロデキストリンの２位水酸基にのみ選択的に生じる。
【００１９】
【実施例】
以下、実施例を挙げ、本発明を更に詳細に説明する。
実施例１
α−シクロデキストリン(0.20g) をN,N-ジメチルホルムアミド(6.0ml) に溶解し、モレキュラーシーブス４Ａ(0.50g) 及びp-トルエンスルホニルイミダゾール（アルドリッチ社）(0.039g)を加え、室温で攪拌した。60時間後、減圧ろ過し、ろ液を減圧濃縮した。残留物をＯＤＳクロマトグラフィーに付しメタノール：水＝１０：９０、つづいてメタノール：水＝２０：８０で溶出し、2-O-p-トルエンスルホニル -α- シクロデキストリン(0.083g)を得た。 (α- シクロデキストリンからの収率: 35％) 。
【００２０】
実施例２
N,N-ジメチルホルムアミドをN,N-ジメチルアセトアミド(6.0ml) に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-トルエンスルホニル -α- シクロデキストリンを収率30％で得た。
実施例３
N,N-ジメチルホルムアミド(6.0ml) をN,N-ジメチルホルムアミド(3.6ml) と水(2.4ml) の混合溶媒に換え、反応時間を 100時間とした以外は実施例１と同じ条件で反応操作を行い、2-O-p-トルエンスルホニル -α- シクロデキストリンを収率: 31％で得た。
【００２１】
実施例４
モレキュラーシーブス４Ａをモレキュラーシーブス３Ａ(0.50g) に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-トルエンスルホニル -α- シクロデキストリンを収率33％で得た。
実施例５
モレキュラーシーブス４Ａをモレキュラーシーブス13Ｘ(0.50g) に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-トルエンスルホニル -α- シクロデキストリンを収率30％で得た。
【００２２】
実施例６
p-トルエンスルホニルイミダゾールを下記の参考例２で得たp-t-ブチルベンゼンスルホニルイミダゾール(0.046g)に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-t-ブチルベンゼンスルホニル -α- シクロデキストリンを収率39％で得た。
実施例７
p-トルエンスルホニルイミダゾールを下記の参考例１で得たp-ニトロベンゼンスルホニルイミダゾール(0.044g)に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-ニトロベンゼンスルホニル -α- シクロデキストリンを収率16％で得た。
【００２３】
実施例８
p-トルエンスルホニルイミダゾールを下記の参考例３で得たベンゾイルイミダゾール(0.030g)に換えた以外は実施例１と同じ条件で反応操作を行い、2-O-p-ベンゾイル -α- シクロデキストリンを収率30％で得た。
実施例９
α- シクロデキストリンをβ- シクロデキストリンに換えた以外は実施例１と同じ条件で反応操作を行ない、2-O-p-トルエンスルホニル -β- シクロデキストリンを収率36％で得た。
【００２４】
参考例１
ｐ−ニトロベンゼスルホニルイミダゾールの合成法
市販のイミダゾール(0.67g) を、60％NaH(0.39g)を含むN,N-ジメチルホルムアミド(15ml)に、氷冷下で攪拌しながら徐々に加え、加え終わってから更に20分攪拌した。その後、p-ニトロベンゼンスルホニルクロリド(2g)を徐々に加え30分攪拌した。反応液を水(50ml)に加え、ベンゼン(30ml)で抽出し、更に水層よりベンゼン(30ml)で２回抽出した。抽出液をあわせ、水で洗浄した後、無水硫酸マグネシウムで脱水し、減圧濃縮した。残さに酢酸エチル及びn-ヘキサンを加え、p-ニトロベンゼンスルホニルイミダゾール(1.5g)の結晶を収率66％で得た。
参考例２
p-t-ブチルベンゼンスルホニルイミダールの合成法
市販のイミダゾール(0.32g) を、60％NaH(0.19g)を含むN,N-ジメチルホルムアミド(15ml)に、氷冷下で攪拌しながら徐々に加え、加え終わってから更に20分攪拌した。その後、p-t-ブチルベンゼンスルホニルクロリド(1.0g)を徐々に加え30分攪拌した。反応液を水(50ml)に加え、ベンゼン(30ml)で抽出し、更に水層よりベンゼン(30ml)で２回抽出した。抽出液をあわせ、水で洗浄した後、無水硫酸マグネシウムで脱水し、減圧濃縮した。残さにn-ヘキサンを加え、p-t-ブチルベンゼンスルホニルイミダゾール(0.81g) の結晶を収率71％で得た。
参考例３
ベンゾイミダゾールの合成法
市販のイミダゾール(1.1g)を、60％NaH(0.63g)を含むN,N-ジメチルホルムアミド(15ml)に、氷冷下で攪拌しながら徐々に加え、加え終わってから更に20分攪拌した。その後、ベンゾイルクロリド(2.0g)を徐々に加え30分攪拌した。反応液を水(50ml)に加え、ベンゼン(30ml)で抽出し、更に水層よりベンゼン(30ml)で２回抽出した。抽出液をあわせ、水で洗浄した後、無水硫酸マグネシウムで脱水し、減圧濃縮した。残さをシリカゲルクロマトグラフィーに付し、酢酸エチル：n-ヘキサン＝１：４で溶出し、ベンゾイルイミダゾール(1.8g)を収率75％で得た。
【００２５】
【発明の効果】
本発明によれば、シクロデキストリンを構成する少なくとも１つのＤ(+)-グルコピラノース単位の２位水酸基を選択的にスルホニル化、またはアシル化したシクロデキストリン誘導体を、簡便に、温和な条件下で、一段階で効率よく製造することができる。
これにより特別な装置、例えば冷却・加熱等の温度調節装置や無水装置、厳密な反応条件、例えば反応溶液のｐＨ調製や無水条件を必要とせず、簡便に収率よく、一段階で、２位水酸基の多種の選択的修飾が可能となる。本発明により、合成効率の悪かった既存の２位修飾シクロデキストリンやこれまで合成できなかった２位修飾シクロデキストリンが簡便に効率よく得られる。本発明は、これまでにはない性質を有するシクロデキストリン誘導体の開発に有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a sulfonylated or acylated cyclodextrin derivative at the 2-position hydroxyl group of at least one D (+)-glucopyranose unit constituting the cyclodextrin.
[0002]
[Prior art]
Cyclodextrins are α-1,4 linked cyclic oligosaccharides composed of D (+)-glucopyranose units. Cyclodextrins and derivatives thereof have a hydrophobic property in the pores derived from the cyclic structure, and have an inclusion ability for hydrophobic compounds. Therefore, it is actively used in various industrial fields. For example, as a food additive that maintains flavor in the food field, as a pharmaceutical material in the pharmaceutical field, as an agent for improving drug administration, improving drug absorption, as a polymer material in the engineering field, The use is done.
Each D (+)-glucopyranose unit constituting cycltodextrin has a 6-position hydroxyl group which is a primary hydroxyl group, a 2-position and a 3-position hydroxyl group which are secondary hydroxyl groups. Cyclodextrin derivatives in which these hydroxyl groups are partially or wholly converted to other substituents have different properties from existing cyclodextrins, with changes in solubility and inclusion ability. New use is expected.
[0003]
In order to convert a hydroxyl group into a desired substituent, it is necessary to selectively perform a substitution reaction on the 6-position, 2-position, and 3-position hydroxyl groups. Various studies have been conducted on these reactions, and modification of the 6-position hydroxyl group has been achieved relatively easily. However, modification of the 2-position and 3-position hydroxyl groups is difficult, and most of the methods achieve the modification of the 2-position or 3-position hydroxyl groups after protecting the 6-position, which is preferred for reactivity.
There are few examples in which the 2-position hydroxyl group is selectively modified directly without protecting the 6-position hydroxyl group. Examples of selective sulfonylation of the 2-position hydroxyl group directly without protecting the 6-position hydroxyl group include Y. Iwakura, K. Uno, F. Toda, S. Onozuka, K. Hattori, and MI Bender, J. Am. Chem. Soc., 1975, 97, 4432-4434. A. Ueno, R. Breslow, Tetrahedron Lett., 1982, 23, 3451-3454. R. Breslow, and AW Czarnik J. Am. Chem. Soc., 1983, 105, 1390-1391. K. Takahashi, K. Hattori, and F. Toda, Tetrahedron Lett. 1984, 25, 3331-3334. K Fujita, S. Nagamura, and T. Imoto, Tetrahedron Lett., 1984, 25, 5673-5676. K. Fujita, S. Ngamura, T. Imoto, T. Tahara and T. Koga, J. Am. Chem. Soc., 1985, 107, 3233-3235. T. Murakami, K. Harata , and S. Morimoto, Tetrahedron Lett., 1987, 28, 321-324. An example of acetylation is disclosed in JP-A-7-90006. These are methods that utilize the inclusion phenomenon of cyclodextrins in water, and methods that require the activation reaction of the 2-position hydroxyl group in an anhydrous solvent.
[0004]
[Problems to be solved by the invention]
The method described in the above document uses the inclusion phenomenon of cyclodextrin in an aqueous system, so that a basic aqueous solution is used as a reaction solvent, or 2-position selectivity occurs only when a specific sulfonylating reagent is used. Alternatively, it is a multistage reaction because it requires an activation reaction of the 2-position hydroxyl group in an anhydrous solvent. Under these conditions, there are problems such as decomposition of the product, deterioration in yield, impossibility of various modifications, and complicated reaction operations.
Accordingly, an object of the present invention is to provide a cyclodextrin derivative in which the 2-position hydroxyl group of at least one D (+)-glucopyranose unit constituting the cyclodextrin is selectively sulfonylated or acylated under simple conditions. An object of the present invention is to provide a method for efficiently producing in one step.
[0005]
[Means for Solving the Problems]
The present inventors have studied various methods for easily and selectively modifying the hydroxyl group at the 2-position of cyclodextrin in a selective and high yield. As a result, when a reagent having an imidazole leaving group is reacted with cyclodextrin in the presence of molecular sieves as a catalyst, the 2-position hydroxyl group of cyclodextrin is selectively sulfonylated or acylated in one step. And the present invention was completed.
[0006]
That is, the present invention reacts cyclodextrin with an imidazole derivative represented by the following formula (1) in the presence of molecular sieves to form the 2-position of at least one D (+)-glucopyranose unit constituting the cyclodextrin. The present invention relates to a method for producing a cyclodextrin derivative characterized in that a cyclodextrin derivative having a hydroxyl group sulfonylated or acylated is obtained.
[0007]
[Chemical 3]

[0008]
(In the formula, R is an unsubstituted or substituted sulfonyl group or an unsubstituted or substituted acyl group.)
Hereinafter, the present invention will be described in detail.
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, cyclodextrin means unsubstituted and substituted α-cyclodextrin (n = 6), unsubstituted and substituted β-cyclodextrin (n = 7), unsubstituted and substituted γ-cyclodextrin (n = 8) Say. The substituted cyclodextrin is a cyclodextrin having a substituent at a position other than the 2-position hydroxyl group of the D (+)-glucopyranose unit constituting the cyclodextrin. For example, the cyclodextrin in which the hydroxyl group at the 3-position and / or 6-position of the cyclodextrin is modified can be mentioned. In addition, according to the production method of the present invention, a cyclodextrin derivative obtained by sulfonylating or acylating the 2-position hydroxyl group of at least one D (+)-glucopyranose unit constituting the starting cyclodextrin can be obtained. The number of introduced sulfonyl groups or acyl groups can be adjusted as appropriate by controlling the reaction conditions. Depending on the conditions, the 2-position hydroxyl group of one D (+)-glucopyranose unit represented by the following formula (2) can be sulfonylated or Acylated cyclodextrin derivatives can be obtained.
[0010]
[Formula 4]

[0011]
(In the formula, R is an unsubstituted or substituted sulfonyl group or an unsubstituted or substituted acyl group.)
A reaction scheme of a method for producing a cyclodextrin derivative in which the 2-position hydroxyl group of one D (+)-glucopyranose unit is substituted is shown below.
[0012]
[Chemical formula 5]

[0013]
In the production method of the present invention, the cyclodextrin is reacted with the imidazole derivative represented by the formula (1). R in Formula (1) is an unsubstituted or substituted sulfonyl group or an unsubstituted or substituted acyl group. Here, the substituent X of the sulfonyl group and the acyl group includes a lower alkyl group (for example, methyl, ethyl, propyl, butyl, etc.), an unsubstituted aromatic group (for example, phenyl, naphthyl), and a lower alkyl group as the substituent. Examples thereof include aromatic groups having a group (for example, methyl, ethyl, propyl, butyl, etc.) or a nitro group.
[0014]
Specific examples of the imidazole derivative represented by the formula (1) are shown below.
Sulfonylimidazole: linear, branched or cyclic aliphatic sulfonylimidazole such as methanesulfonylimidazole, ethanesulfonylimidazole, propanesulfonylimidazole, butanesulfonylimidazole, and p-toluenesulfonylimidazole, t-butylbenzenesulfonylimidazole, Aromatic sulfonylimidazoles such as nitrobenzenesulfonylimidazole and naphthylsulfonylimidazole, which may have a substituent.
Acyl imidazole: linear, branched or cyclic aliphatic carbonyl imidazole such as formyl imidazole, acetyl imidazole, propionyl imidazole, butyryl midazole, valeryl imidazole, pivaloyl imidazole, and aromatic carbonyl imidazole such as benzoyl imidazole It may be.
[0015]
Some imidazole derivatives are commercially available, and even if there are no commercially available products, they can be easily produced by the following method.
Commercially available imidazole is gradually added to N, N-dimethylformamide (15 ml) containing 60% NaH 3 with stirring under ice-cooling, and the mixture is further stirred for 20 minutes after the addition is completed. Thereafter, chlorides such as sulfonyl chloride and acyl chloride are gradually added and stirred for 30 minutes. The reaction solution is added to water, extracted with benzene, and further extracted twice from the aqueous layer with benzene. The extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Substituted imidazole (imidazole derivative) is obtained from the residue.
[0016]
The reaction of the present invention is carried out in the presence of molecular sieves as a catalyst. Examples of molecular sieves include MS3A, MS4A, MS5A, MS13X and the like. The shape may be powder or pellets. In addition, the molecular sieves in this reaction serve as a catalyst for activating the reaction between the imidazole reagent and cyclodextrin, and do not play a role of dehydration as generally used. Accordingly, the molecular sieves used may be either activated for dehydration, inactive for dehydration, or containing a large amount of water. That is, the molecular sieves may be either activated molecular sieves or inactivated molecular sieves.
[0017]
The reaction of the present invention is preferably carried out in the presence of a solvent, and any solvent that does not participate in the reaction can be used. However, from the viewpoint of good solubility of the reactant, an anhydrous or water-containing basic organic solvent is suitable. Examples of basic organic solvents include amide polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, and pyridine. In addition, since this reaction does not require anhydrous conditions, the solvent may contain moisture. Similarly, the cyclodextrin may be either dried or containing water.
The reaction of the present invention can usually be carried out at room temperature, and can also be carried out at an elevated temperature or cooling in consideration of the reaction yield, the number of introduced substituents, and the like. The reaction time can be appropriately determined in consideration of the reaction yield and the like. For example, the reaction time is suitably in the range of 10 to 200 hours.
[0018]
The amount of imidazole derivative added depends on the reaction conditions such as the number of substituents introduced to the target cyclodextrin, the reaction temperature and reaction time, the solvent used, the weight ratio of cyclodextrin and molecular sieves, etc. In addition, it is appropriate to add to the reaction system in the range of 1 to 10 mol. Preferably, it is preferable to use an imidazole derivative equivalent to the number of moles of substituents to be introduced per mole of cyclodextrin.
In the reaction system, it is desirable that the cyclodextrin is completely dissolved in the solvent, and the higher the dissolved cyclodextrin concentration, the more efficiently the reaction can be performed. Therefore, the amount of the solvent used is suitably in the range of 5 to 100 parts by weight with respect to 1 part by weight of cyclodextrin. Preferably, it is desirable that the amount of the cyclodextrin is saturated at the cyclodextrin used, the type of solvent, and the reaction temperature.
In addition, the larger the amount of molecular sieve used, the more efficiently the substituent can be introduced, the yield of the cyclodextrin derivative can be improved, and the reaction time can be shortened. Therefore, the amount of molecular sieve can be used without limitation as long as it does not hinder the stirring system of the apparatus used for the reaction. However, practically, it is appropriate to be in the range of 0.01 to 0.2 parts by weight with respect to 1 part by weight of the solvent. In addition to adding molecular sieves to the reaction solution, the reaction solution can be added to a column packed with molecular sieves and reacted in the column.
According to the reaction of the present invention, sulfonylation or acylation occurs selectively only at the 2-position hydroxyl group of cyclodextrin.
[0019]
【Example】
EXAMPLES Hereinafter, an Example is given and this invention is demonstrated still in detail.
Example 1
Dissolve α-cyclodextrin (0.20 g) in N, N-dimethylformamide (6.0 ml), add molecular sieves 4A (0.50 g) and p-toluenesulfonylimidazole (Aldrich) (0.039 g), and stir at room temperature. did. After 60 hours, the solution was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was subjected to ODS chromatography and eluted with methanol: water = 10: 90, followed by methanol: water = 20: 80 to give 2-Op-toluenesulfonyl-α-cyclodextrin (0.083 g). (Yield from α-cyclodextrin: 35%).
[0020]
Example 2
The reaction was conducted under the same conditions as in Example 1 except that N, N-dimethylformamide was replaced with N, N-dimethylacetamide (6.0 ml), yielding 30% yield of 2-Op-toluenesulfonyl-α-cyclodextrin. I got it.
Example 3
The reaction was carried out under the same conditions as in Example 1 except that N, N-dimethylformamide (6.0 ml) was replaced with a mixed solvent of N, N-dimethylformamide (3.6 ml) and water (2.4 ml) and the reaction time was 100 hours. The operation was performed to obtain 2-Op-toluenesulfonyl-α-cyclodextrin in a yield of 31%.
[0021]
Example 4
The reaction was carried out under the same conditions as in Example 1 except that molecular sieve 4A was changed to molecular sieve 3A (0.50 g) to obtain 2-Op-toluenesulfonyl-α-cyclodextrin in a yield of 33%.
Example 5
The reaction was carried out under the same conditions as in Example 1 except that molecular sieves 4A were replaced with molecular sieves 13X (0.50 g) to obtain 2-Op-toluenesulfonyl-α-cyclodextrin in a yield of 30%.
[0022]
Example 6
The reaction was carried out under the same conditions as in Example 1 except that p-toluenesulfonylimidazole was changed to pt-butylbenzenesulfonylimidazole (0.046 g) obtained in Reference Example 2 below, and 2-Opt-butylbenzenesulfonyl-α -Cyclodextrin was obtained in 39% yield.
Example 7
The reaction was conducted under the same conditions as in Example 1 except that p-toluenesulfonylimidazole was replaced with p-nitrobenzenesulfonylimidazole (0.044 g) obtained in Reference Example 1 below, and 2-Op-nitrobenzenesulfonyl-α-cyclo Dextrin was obtained with a yield of 16%.
[0023]
Example 8
The reaction was carried out under the same conditions as in Example 1 except that p-toluenesulfonylimidazole was replaced with benzoylimidazole (0.030 g) obtained in Reference Example 3 below, yielding 2-Op-benzoyl-α-cyclodextrin. Obtained at 30%.
Example 9
The reaction operation was carried out under the same conditions as in Example 1 except that α-cyclodextrin was replaced with β-cyclodextrin, and 2-Op-toluenesulfonyl-β-cyclodextrin was obtained in a yield of 36%.
[0024]
Reference example 1
Method for synthesizing p-nitrobenzensulfonylimidazole Commercially available imidazole (0.67 g) was gradually added to N, N-dimethylformamide (15 ml) containing 60% NaH (0.39 g) with stirring under ice cooling. After completion, the mixture was further stirred for 20 minutes. Thereafter, p-nitrobenzenesulfonyl chloride (2 g) was gradually added and stirred for 30 minutes. The reaction solution was added to water (50 ml), extracted with benzene (30 ml), and further extracted twice with benzene (30 ml) from the aqueous layer. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue to obtain crystals of p-nitrobenzenesulfonylimidazole (1.5 g) in a yield of 66%.
Reference example 2
Method for synthesizing pt-butylbenzenesulfonyl imidazole Commercially available imidazole (0.32 g) was gradually added to N, N-dimethylformamide (15 ml) containing 60% NaH (0.19 g) with stirring under ice cooling. After the addition was completed, the mixture was further stirred for 20 minutes. Thereafter, pt-butylbenzenesulfonyl chloride (1.0 g) was gradually added and stirred for 30 minutes. The reaction solution was added to water (50 ml), extracted with benzene (30 ml), and further extracted twice with benzene (30 ml) from the aqueous layer. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-Hexane was added to the residue to obtain crystals of pt-butylbenzenesulfonylimidazole (0.81 g) in a yield of 71%.
Reference example 3
Method for synthesizing benzimidazole Commercially available imidazole (1.1 g) was gradually added to N, N-dimethylformamide (15 ml) containing 60% NaH (0.63 g) with stirring under ice-cooling. Stir for 20 minutes. Thereafter, benzoyl chloride (2.0 g) was gradually added and stirred for 30 minutes. The reaction solution was added to water (50 ml), extracted with benzene (30 ml), and further extracted twice with benzene (30 ml) from the aqueous layer. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate: n-hexane = 1: 4 to obtain benzoylimidazole (1.8 g) in a yield of 75%.
[0025]
【The invention's effect】
According to the present invention, a cyclodextrin derivative in which the 2-position hydroxyl group of at least one D (+)-glucopyranose unit constituting the cyclodextrin is selectively sulfonylated or acylated is easily and mildly treated under mild conditions. , Can be manufactured efficiently in one step.
This eliminates the need for special devices such as temperature control devices such as cooling and heating, and anhydrous devices, and strict reaction conditions such as pH adjustment and anhydrous conditions of the reaction solution, and it is easy to obtain a high yield in a single step. Various selective modifications of the hydroxyl group are possible. According to the present invention, an existing 2-position modified cyclodextrin with poor synthesis efficiency and a 2-position modified cyclodextrin that could not be synthesized can be easily and efficiently obtained. The present invention is useful for the development of cyclodextrin derivatives having unprecedented properties.

Claims (4)

Cyclodextrin and an imidazole derivative represented by the following formula (1) are reacted in the presence of molecular sieves to sulfonylate or acylate the 2-position hydroxyl group of at least one D (+)-glucopyranose unit constituting the cyclodextrin. A process for producing a cyclodextrin derivative, characterized in that a cyclodextrin derivative obtained is obtained.

(In the formula, R is an unsubstituted or substituted sulfonyl group or an unsubstituted or substituted acyl group.) The production method according to claim 1, wherein the cyclodextrin derivative is a compound represented by the following formula (2).

(In the formula, R is an unsubstituted or substituted sulfonyl group or an unsubstituted or substituted acyl group.) The production method according to claim 1 or 2, wherein the molecular sieve is an activated molecular sieve or an inactivated molecular sieve. The production method according to any one of claims 1 to 3, wherein the reaction is carried out in an anhydrous or hydrous basic organic solvent.