JPH06220105A - Cyclodextrain derivative and its production - Google Patents

Abstract

PURPOSE:To surely produce a cyclodextrin derivative having chemically modified hydroxyl groups and high clathrating capability stepwise in high yield without causing side reactions by introducing formyl groups into all 6-hydroxyl groups. CONSTITUTION:The cyclodextrin derivative expressed by formula (n is 6, 7 or 8) is produced by converting all hydroxyl groups of 6-site with CHO groups. It can be produced by benzylating or allylating 2- and 3-hydroxyl groups of (6-0-t-butyldimethylsilyl)cyclodextrin, desilylating the product and oxidizing the 6-hydroxyl groups to formyl groups.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は新規なシクロデキストリ
ン誘導体及びその製造方法に関するものである。FIELD OF THE INVENTION The present invention relates to a novel cyclodextrin derivative and a method for producing the same.

【０００２】[0002]

【従来の技術】シクロデキストリンは分子内に疎水性の
空洞を有し、外側は親水性で水中油型ミセルに似た機能
を示す化合物である。このようなシクロデキストリンは
その空洞径に応じて疎水性のゲスト分子を取り込み水溶
液中で複合体を形成し、調製法によっては固体の包接化
合物を単離することもできる。この立体選択的な相互作
用によりゲスト分子の物理化学的性質を微妙に変化させ
ることができるため、製剤等への有効利用が期待でき、
各方面で種々に利用され、またその利用が図られている
化合物である。Cyclodextrin is a compound that has a hydrophobic cavity in its molecule, is hydrophilic on the outside, and functions like an oil-in-water micelle. Such a cyclodextrin incorporates a hydrophobic guest molecule depending on its cavity diameter to form a complex in an aqueous solution, and a solid inclusion compound can be isolated depending on the preparation method. This stereoselective interaction allows the physicochemical properties of the guest molecule to be subtly changed, so that it can be expected to be effectively used in formulations, etc.
It is a compound that has been and is being used in various ways in various fields.

【０００３】特にシクロデキストリンの２，３又は６位
の水酸基を部分的に残してなるシクロデキストリン誘導
体の場合は、その水酸基との相互作用により包接能が大
幅に変化するため、ゲスト分子の種類、その物性等を大
きく変化させうることが期待できる。Particularly, in the case of a cyclodextrin derivative in which the hydroxyl group at the 2, 3 or 6 position of cyclodextrin is partially left, the inclusion ability is significantly changed by the interaction with the hydroxyl group, so that the type of guest molecule is different. It can be expected that the physical properties and the like can be greatly changed.

【０００４】例えばCan. J. Chem., 52 3905-3912 (197
4)にはシクロデキストリンの６位に−ＣＨＯ基を有する
ものが記載されている。For example, Can. J. Chem., 52 3905-3912 (197
In 4), cyclodextrin having a -CHO group at the 6-position is described.

【０００５】このようなシクロデキストリン誘導体に用
いられる中間物質の合成については、J. Carbohydr. Ch
em.,7 293-308 (1988) ; Carbohydr. Res., 187 203-22
1 (1989) ; Carbohydr. Res., 192 366-369 (1989)等の
論文に詳細に記載されている。Regarding the synthesis of the intermediate substance used for such a cyclodextrin derivative, J. Carbohydr. Ch.
em., 7 293-308 (1988); Carbohydr. Res., 187 203-22
1 (1989); Carbohydr. Res., 192 366-369 (1989) and others.

【０００６】[0006]

【発明が解決しようとする課題】しかしながら、上記文
献に記載される６位に−ＣＨＯ基を有するシクロデキス
トリン誘導体は６位の水酸基のうち１個を−ＣＨＯ基と
したものであり、これら６位すべての水酸基を−ＣＨＯ
基とする等した化合物については上記文献も含め全く報
告はない。従って、このような化合物の場合更に水酸基
との相互作用が変化するため包接現象の顕著な変化が予
想される。However, the cyclodextrin derivative having a -CHO group at the 6-position described in the above literature is one in which one of the hydroxyl groups at the 6-position is a -CHO group. -OH for all hydroxyl groups
There are no reports about the compounds such as the bases including the above-mentioned documents. Therefore, in the case of such a compound, the interaction with the hydroxyl group is further changed, so that a remarkable change in the inclusion phenomenon is expected.

【０００７】すなわち本発明の目的は６位の水酸基のす
べてを−ＣＨＯ基としたシクロデキストリン誘導体及び
該誘導体の製造方法を提供することにある。That is, an object of the present invention is to provide a cyclodextrin derivative in which all of the 6-position hydroxyl groups are -CHO groups and a method for producing the derivative.

【０００８】[0008]

【課題を解決するための手段】本発明の上記目的は、下
記式で表わされるシクロデキストリン誘導体、及び（６
−Ｏ−tert−ブチルジメチルシリル）シクロデキストリ
ンの２位及び３位の水酸基をベンジル化又はアリル化し
た後に、脱シリル化し、次いで６位の水酸基を酸化し、
ホルミル基とすることを特徴とするシクロデキストリン
誘導体の製造方法、により達成される。The above object of the present invention is to provide a cyclodextrin derivative represented by the following formula:
-O-tert-butyldimethylsilyl) cyclodextrin is benzylated or allylated at the 2- and 3-position hydroxyl groups, followed by desilylation and then oxidation at the 6-position hydroxyl group,
It is achieved by a method for producing a cyclodextrin derivative, which comprises a formyl group.

【０００９】[0009]

【化２】 式中、ｎは６，７又は８である。[Chemical 2] In the formula, n is 6, 7 or 8.

【００１０】以下に本発明を更に具体的に説明する。The present invention will be described in more detail below.

【００１１】本発明において、シクロデキストリンはｎ
が６のものをα−シクロデキストリン、ｎが７のものを
β−シクロデキストリン、ｎが８のものをγ−シクロデ
キストリンという。In the present invention, cyclodextrin is n
6 is referred to as α-cyclodextrin, n is referred to as β-cyclodextrin, and n is referred to as γ-cyclodextrin.

【００１２】以下に、本発明のシクロデキストリン誘導
体の具体的反応例を示す。但し以下場合によりシクロデ
キストリンをＣＤと略記する。Specific reaction examples of the cyclodextrin derivative of the present invention are shown below. However, in the following cases, cyclodextrin is abbreviated as CD.

【００１３】[0013]

【化３】 [Chemical 3]

【００１４】上記反応は具体的には以下のように行なわ
れる。 反応［１］ β−ＣＤ（ｎ＝７）を脱水ピリジン中に溶解し、窒素雰
囲気下０〜５℃に冷却する。次いで脱水ピリジンに溶解
した ^tＢＤＭＳｉＣｌを滴下し、滴下終了後０〜５℃で
１時間、室温で12時間攪拌する。反応終了後大量の水よ
り再沈殿を行ない沈殿を濾別、よく水洗し乾燥する。そ
の後シリカゲルカラムクロマトグラフィーにより精製し
得られた［Ａ］はエタノールより３回再結晶を行なう。
（収率：約80％）The above reaction is specifically carried out as follows. Reaction [1] β-CD (n = 7) is dissolved in dehydrated pyridine and cooled to 0 to 5 ° C under a nitrogen atmosphere. Then, ^t BDMSiCl dissolved in dehydrated pyridine is added dropwise, and after completion of the addition, the mixture is stirred at 0 to 5 ° C for 1 hour and at room temperature for 12 hours. After completion of the reaction, reprecipitation is carried out with a large amount of water, the precipitate is filtered off, washed well with water and dried. [A] obtained by purification by silica gel column chromatography is then recrystallized from ethanol three times.
(Yield: about 80%)

【００１５】反応［２］ ［Ａ］を脱水ＤＭＦに溶解後、窒素雰囲気下室温でＮａ
Ｈを添加する。次いで系を０〜５℃に冷却し臭化ベンジ
ルをゆっくり滴下し、滴下終了後ヨウ化ナトリウムを加
え０〜５℃で６時間、室温で48時間攪拌する。反応終了
後メタノールを加え攪拌、次いで不溶物を濾別、濾液に
塩化メチレンを加え１Ｍ−Ｈ₂ ＳＯ₄ 、水の順で洗浄し
有機層を乾燥後減圧下40℃以下で濃縮する。残渣に少量
のＤＭＦを加えメタノールより再沈殿を行ない、析出し
た沈殿物はエタノールより繰り返し再結晶し［Ｂ］を得
る。（収率：約60％）Reaction [2] [A] was dissolved in dehydrated DMF, and then Na was added at room temperature under a nitrogen atmosphere.
Add H. Then, the system is cooled to 0 to 5 ° C, benzyl bromide is slowly added dropwise, and after completion of the addition, sodium iodide is added and the mixture is stirred at 0 to 5 ° C for 6 hours and at room temperature for 48 hours. After completion of the reaction, methanol is added and the mixture is stirred, then the insoluble matter is filtered off, methylene chloride is added to the filtrate, and the mixture is washed with 1M-H ₂ SO ₄ and water in this order. The organic layer is dried and then concentrated under reduced pressure at 40 ° C. or lower. A small amount of DMF is added to the residue to reprecipitate from methanol, and the deposited precipitate is repeatedly recrystallized from ethanol to obtain [B]. (Yield: about 60%)

【００１６】反応［３］ ［Ｂ］を脱水ＴＨＦに溶解し、室温下１Ｍ−（ｎ−Ｃ₄
Ｈ₉ ）₄ Ｎ⁺ Ｆ^- のＴＨＦ溶液をゆっくりと滴下、滴下
終了後少しずつ加温し還流下24時間反応させる。反応終
了後放冷し、減圧下ＴＨＦを留去する。残渣は少量のエ
タノールに溶解し大量の水より再沈殿を行ない、シリカ
ゲルカラムクロマトグラフィーにより精製し［Ｃ］を得
る。（収率：約65％）Reaction [3] [B] was dissolved in dehydrated THF, and the solution was dissolved in 1M- (n-C ₄₎ at room temperature.
A THF solution of H ₉ ) ₄ N ⁺ F ⁻ is slowly added dropwise, and after completion of the addition, the mixture is gradually heated and reacted under reflux for 24 hours. After completion of the reaction, the mixture is allowed to cool and THF is distilled off under reduced pressure. The residue is dissolved in a small amount of ethanol, reprecipitated from a large amount of water, and purified by silica gel column chromatography to obtain [C]. (Yield: about 65%)

【００１７】反応［４］ ［Ｉ］法 ［Ｃ］をベンゼン／ＤＭＳＯ＝１／１に室温
で溶解し、その系に脱水ピリジン、トリフルオロ酢酸、
そしてＤＣＣ（ジシクロヘキシルカルボジイミド）を加
える。添加後室温下36時間攪拌する。反応終了後ベンゼ
ンを加え沈殿物を濾別する。濾液は水で洗浄し有機層は
乾燥後濃縮する。残渣はシリカゲルカラムクロマトグラ
フィーにより精製し［Ｄ］を得る。（収率：約70％）Reaction [4] Method [I] Method [C] is dissolved in benzene / DMSO = 1/1 at room temperature, and dehydrated pyridine, trifluoroacetic acid, and
Then DCC (dicyclohexylcarbodiimide) is added. After the addition, the mixture is stirred at room temperature for 36 hours. After completion of the reaction, benzene is added and the precipitate is filtered off. The filtrate is washed with water, the organic layer is dried and then concentrated. The residue is purified by silica gel column chromatography to obtain [D]. (Yield: about 70%)

【００１８】［II］法 脱水塩化メチレンと塩化オキサ
リル中に塩化メチレンに溶解したＤＭＳＯを加え次いで
［Ｃ］を溶解した塩化メチレン溶液をゆっくりと滴下す
る。滴下終了後−50〜−60℃に冷却し、１時間攪拌後そ
の系にトリエチルアミンを加えさらに30分攪拌、その後
室温まで放置し水を加え塩化メチレンで抽出、有機層は
水洗後乾燥し濃縮する。残渣はシリカゲルカラムクロマ
トグラフィーにより精製［Ｄ］を得る。（収率：約55
％）[II] Method DMSO dissolved in methylene chloride is added to dehydrated methylene chloride and oxalyl chloride, and then a methylene chloride solution containing [C] is slowly added dropwise. After the addition is complete, cool to -50 to -60 ° C, stir for 1 hour, add triethylamine to the system and stir for another 30 minutes, then allow to stand at room temperature and add water, extract with methylene chloride, wash organic layer with water, dry and concentrate. . The residue is purified by silica gel column chromatography to obtain purified [D]. (Yield: about 55
%)

【００１９】［III ］法 酸化クロム−ピリジン錯体を
ＣＨ₂ Ｃｌ₂ に懸濁させ室温で［Ｃ］のＣＨ₂ Ｃｌ₂ 溶
液をゆっくりと滴下する。滴下終了後３時間撹拌、沈殿
物を濾別、濾液をＮａＯＨ水溶液、ＨＣｌ、水の順で洗
浄し、乾燥後減圧下ＣＨ₂ Ｃｌ₂ を留去する。残渣をシ
リカゲルカラムクロマトグラフィーにより精製し［Ｄ］
を得る。（収率：約65％）[III] Method A chromium oxide-pyridine complex is suspended in CH ₂ Cl ₂ and a CH ₂ Cl ₂ solution of [C] is slowly added dropwise at room temperature. After completion of dropping, the mixture is stirred for 3 hours, the precipitate is filtered off, the filtrate is washed with NaOH aqueous solution, HCl and water in this order, and after drying, CH ₂ Cl ₂ is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [D].
To get (Yield: about 65%)

【００２０】［IV］法 クロロクロム酸ピリジニウム
（ＰＣＣ）と酢酸ナトリウムをＣＨ₂ Ｃｌ₂ に懸濁さ
せ、撹拌しながら室温下で［Ｃ］のＣＨ₂ Ｃｌ₂ 溶液を
ゆっくりと滴下する。滴下終了後３時間撹拌、反応終了
後沈殿物を濾別し、濾液を水で洗浄後、乾燥し減圧下Ｃ
Ｈ₂ Ｃｌ₂ を留去する。残渣をシリカゲルカラムクロマ
トグラフィーにより精製し［Ｄ］を得る。（収率：約60
％）[IV] Method Pyridinium chlorochromate (PCC) and sodium acetate are suspended in CH ₂ Cl _2, and a CH ₂ Cl ₂ solution of [C] is slowly added dropwise at room temperature with stirring. After completion of dropping, the mixture was stirred for 3 hours, and after completion of the reaction, the precipitate was filtered off, the filtrate was washed with water, dried and dried under reduced pressure C
H ₂ Cl ₂ is distilled off. The residue is purified by silica gel column chromatography to obtain [D]. (Yield: about 60
%)

【００２１】反応［５］ ［Ｄ］をエタノール／酢酸＝２／１溶液に溶解し、10％
Ｐｄ／Ｃを触媒として添加後水素添加を行なう（40℃，
５kg／cm² ）。水素圧が減少しなくなった時点で反応を
終了させ、Ｐｄ／Ｃを濾別、濾液を減圧下濃縮、残渣を
少量のＤＭＦに溶解し大量のアセトンより再沈殿を行な
う。沈殿物は減圧乾燥し［Ｅ］を得る。（収率：約90
％）Reaction [5] [D] was dissolved in an ethanol / acetic acid = 2/1 solution to give 10%.
After adding Pd / C as a catalyst, hydrogenation is performed (40 ° C,
5 kg / cm ² ). When the hydrogen pressure has stopped decreasing, the reaction is terminated, Pd / C is filtered off, the filtrate is concentrated under reduced pressure, the residue is dissolved in a small amount of DMF, and reprecipitation is performed from a large amount of acetone. The precipitate is dried under reduced pressure to obtain [E]. (Yield: about 90
%)

【００２２】[0022]

【発明の効果】本発明の製造方法により、６位の水酸基
すべてにホルミル基を導入したＣＤ誘導体を提供するこ
とができる。EFFECTS OF THE INVENTION The production method of the present invention can provide a CD derivative having a formyl group introduced into all hydroxyl groups at the 6-position.

【００２３】また、本発明によれば段階ごとにＣＤの持
つ水酸基を狙って化学修飾するために確実に目的物が得
られる。更に高価な試薬を用いず、しかも個々の反応に
おいて副反応が生じにくいため収率が高く、−ＣＨ₂ Ｏ
Ｈ基が−ＣＨＯ基になることで水溶性も大きく変化しＣ
Ｄの包接能も大きく変化すると期待される。Further, according to the present invention, the target compound can be reliably obtained because the hydroxyl group of CD is chemically modified aiming at each step. Since more expensive reagents are not used and side reactions are unlikely to occur in individual reactions, the yield is high, and -CH ₂ O
When the H group becomes a -CHO group, the water solubility also changes significantly, and C
It is expected that the inclusion ability of D will also change greatly.

Claims (2)

【特許請求の範囲】[Claims] 【請求項１】 下記式で表わされるシクロデキストリン
誘導体。 【化１】 式中、ｎは６，７又は８である。1. A cyclodextrin derivative represented by the following formula. [Chemical 1] In the formula, n is 6, 7 or 8. 【請求項２】 （６−Ｏ−tert−ブチルジメチルシリ
ル）シクロデキストリンの２位及び３位の水酸基をベン
ジル化又はアリル化した後に、脱シリル化し、次いで６
位の水酸基を酸化し、ホルミル基とすることを特徴とす
るシクロデキストリン誘導体の製造方法。2. A hydroxyl group at the 2- and 3-positions of (6-O-tert-butyldimethylsilyl) cyclodextrin is benzylated or allylated, followed by desilylation and then 6-
A method for producing a cyclodextrin derivative, which comprises oxidizing a hydroxyl group at a position to form a formyl group.