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

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cyclodextrin derivative and a method for producing the same.

[0002]

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.

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.

For example, Can. J. Chem., 52 3905-3912 (197
In 4), cyclodextrin having a -CHO group at the 6-position is described.

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]

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.

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]

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]

[Chemical 2] In the formula, n is 6, 7 or 8.

The present invention will be described in more detail below.

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.

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]

[Chemical 3]

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%)

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%)

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%)

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%)

[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
%)

[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%)

[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
%)

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]

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.

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)

[Claims] 1. A cyclodextrin derivative represented by the following formula. [Chemical 1] In the formula, n is 6, 7 or 8. 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.