JPH06271602A - Cyclodextrin derivative and method for producing the same - Google Patents

Abstract

PURPOSE:To obtain a CD derivative, having a structure in which hydroxyl group is substituted with cyano group, capable of surely providing the objective substance by aiming at and chemically modifying the hydroxyl group in each stage, producible with hardly any side reaction without using an expensive reagent and greatly changing the clathration ability. CONSTITUTION:This cyclodextrin derivative is expressed by the formula [(n) is 6, 7 or 8] and obtained by halogenating hydroxyl group at the 6-position of cyclodextrin, then reacting the resultant halogenated hydroxyl group with an alkali cyanide and cyanogenating the halogenated hydroxyl group at the 6-position. Otherwise, the hydroxyl group at the 6-position is protected with a protecting group and the resultant protected cyclodextrin is made to react with copper cyanide to cyanogenate the 6-position. The hydroxyl groups at the 2- and the 3-positions of (6-O-tert-butyldimethylsilyl)cyclodextrin are protected with protecting groups and then allowed to react with the alkali cyanide. Thereby, the 6-position is cyanogenated.

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 or is substituted with another substituent, the interaction with the hydroxyl group or other substituents. As a result, the inclusion capacity is significantly changed, so that it is expected that the type of guest molecule, its physical properties, etc. can be changed significantly.

Therefore, various studies have been made on cyclodextrin derivatives in which such a hydroxyl group is substituted with another substituent.

[0005]

However, with respect to the derivative having a cyano group, --NH ₂ , --COOH,
Despite their usefulness in conversion to cyclodextrin derivatives having -CHO groups, their syntheses have never been reported.

Therefore, an object of the present invention is to provide a cyclodextrin derivative in which a hydroxyl group is substituted with a cyano group, and a method for producing these derivatives.

[0007]

The object of the present invention is achieved by providing a cyclodextrin derivative represented by the following formula [I].

[0008]

[Chemical 2] Further, the above object of the present invention is: (1) Production of a cyclodextrin derivative, which comprises halogenating the hydroxyl group at the 6-position of cyclodextrin, and then reacting this with an alkali cyanide to cyanate the 6-position. Method, (2)
A method for producing a cyclodextrin derivative, which comprises reacting cyclodextrin having a hydroxyl group at the 6-position protected with a protecting group with copper cyanide to cyanate the 6-position, or (3) (6-O-tert- A cyclodextrin derivative characterized by protecting the hydroxyl groups at the 2- and 3-positions of (butyldimethylsilyl) cyclodextrin with a protecting group, desilylating, and then reacting with an alkali cyanide to cyanate the 6-position. And a manufacturing method.

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.

Preferred examples of the alkali cyanide used in the present invention include sodium cyanide and potassium cyanide.

Specific reaction examples of the cyclodextrin derivative of the present invention represented by the formula [I] will be 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 DMF at room temperature, and then imidazole is added and stirred. After about 1 hour, dichlorophenylphosphine was added, followed by bromine (X = Br),
After the addition, stir at room temperature for 1 hour. After completion of the reaction, DMF is distilled off under reduced pressure, acetone is added to the residue and the mixture is stirred, and the precipitate is separated by filtration. The desired product is obtained by dissolving again in a small amount of DMF and reprecipitating from a large amount of water. (Yield: about 90%)

Reaction [2] [A] was dissolved in dehydrated DMSO and the system was added with NaC at room temperature.
Add N (or KCN). 2 at 80-90 ° C after addition
Stir for hours. After completion of the reaction, the precipitate is filtered off, the filtrate is concentrated under reduced pressure, and the residue is reprecipitated from a large amount of water. The precipitate is filtered off, dissolved again in a small amount of DMSO, and reprecipitated from a large amount of water to obtain [B]. (Yield: about 85%)

Reaction [3] β-CD (n = 7) was dissolved in dehydrated pyridine, and p-CD was added at room temperature.
-Toluenesulfonic acid chloride pyridine solution is added dropwise, and after completion of the addition, the mixture is stirred for 6 hours. After completion of the reaction, water is added to the system, and the solvent is distilled off under reduced pressure at 40 ° C or lower. The residue is neutralized and then separated using acetonitrile / water system using reverse phase HPLC to obtain [C]. (Yield: about 35%)

Reaction [4] [C] was dissolved in dehydrated DMSO and CuC was added to the system at room temperature.
Add N, KI. After the addition, the mixture is stirred at 80 to 90 ° C for 8 hours. After the reaction was completed, the precipitate was filtered off and the filtrate was concentrated under reduced pressure.
The residue is reprecipitated from a large amount of water. The precipitate is filtered off,
[B] is obtained by dissolving again in a small amount of DMSO and reprecipitating from a large amount of water. (Yield: about 80%)

Reaction [5] 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. After that, the product is purified by silica gel column chromatography, and the obtained [D] is repeatedly recrystallized from ethanol. (Yield: about 80%)

Reaction [6] After dissolving [D] in dehydrated DMF, 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, and the organic layer is dried and concentrated under reduced pressure at 40 ° C. or lower. Add a small amount of DMF to the residue and reprecipitate from methanol,
The deposited precipitate is repeatedly recrystallized from ethanol to obtain [E]. (Yield: about 60%)

Reaction [7] Dissolve [E] in THF and add 1M- (n-C ₄ H) at room temperature.
_{9) 4} N ⁺ F ^- THF was added and slowly warmed After completion of the dropwise addition, the reaction under reflux for 24 hours. T after reaction
HF is distilled off under reduced pressure, the residue is extracted with a CH ₂ Cl ₂ / water system, and the CH ₂ Cl ₂ layer is dried and then concentrated. The residue is then purified by silica gel column chromatography [F].
To get (Yield: about 80%)

Reaction [8] [F] is dissolved in carbon tetrachloride, and triphenylphosphine and NaCN (or KCN) are added at room temperature. After the addition, the mixture is slowly heated and reacted under reflux for 4 hours. After completion of the reaction, the precipitate is filtered off, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain [G]. (Yield: about 75%)

Reaction [9] [G] was dissolved in ethanol / acetic acid = 2/1 to obtain 10% P
After adding d / C as a catalyst, hydrogenation is performed (40 ° C, 5
kg / cm ² ). The reaction is terminated when the hydrogen pressure does not decrease, Pd / C is filtered off, the filtrate is concentrated under reduced pressure, and the residue is reprecipitated from a large amount of water to obtain [B]. (Yield: about 90%)

The above reaction [1] can also be carried out by the method described in Japanese Patent Application No. 4-218327.

As a method for synthesizing a substance having an Si group used for producing the cyclodextrin derivative of the present invention, J. Carbohy
dr. Chem., 7 293-308 (1988), Carbohydr. Res., 187
Takeo et al.'S paper 203-221 (1989) and Carbohydr. Res., 1
92 366-369 (1989) and the like.

As a method for synthesizing a substance having a Ts group, Ch
Em. Pharm. Bull., 39 2505-2508 (1991) etc.

[0026]

According to the production method of the present invention, it is possible to provide a cyclodextrin derivative in which the hydroxyl group at the 6-position is substituted with a cyano group.

According to the present invention, since the hydroxyl group of CD is aimed at each step and chemically modified, the intended product can be obtained reliably. In addition, since expensive reagents are not used and side reactions are unlikely to occur in individual reactions, the yield is high. Furthermore, it is expected that the inclusion of -CN group will greatly change the water solubility and the CD inclusion ability. Since the —CN group can be converted into various functional groups by a simple reaction, many CD derivatives can be easily synthesized.

Claims (4)

[Claims] 1. A cyclodextrin derivative represented by the following formula [I]. [Chemical 1] 2. A method for producing a cyclodextrin derivative, which comprises halogenating a hydroxyl group at the 6-position of cyclodextrin, and reacting this with an alkali cyanide to cyanate the 6-position. 3. A method for producing a cyclodextrin derivative, which comprises reacting cyclodextrin having a hydroxyl group at the 6-position protected with a protective group with copper cyanide to cyanate the 6-position. 4. A hydroxyl group at the 2-position and 3-position of (6-O-tert-butyldimethylsilyl) cyclodextrin is protected with a protecting group, desilylated, and then reacted with an alkali cyanide to convert the 6-position. A method for producing a cyclodextrin derivative, which comprises cyanating.