JPH07102003A - Method for producing cyclodextrin derivative - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] To provide a method for obtaining an acylated derivative of cyclodextrin in a short time and in a high yield. A method for producing a cyclodextrin derivative, which comprises reacting a cyclodextrin or a cyclodextrin derivative with an acid cyanide such as acetyl cyanide for acylation.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an acylated derivative of cyclodextrin.

[0002]

2. Description of the Related Art Cyclodextrin (C
(Abbreviated as D) is a compound that has a hydrophobic cavity in the molecule, is hydrophilic on the outside, and functions similar to an oil-in-water micelle. Such a CD may incorporate a hydrophobic guest molecule depending on its cavity diameter to form a complex in an aqueous solution, and a solid inclusion compound may 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 used effectively in pharmaceutical preparations, and it is widely used in various fields and is being used. Is.

Particularly, in the case of a cyclodextrin derivative in which the hydroxyl groups at the 2, 3 or 6-positions of cyclodextrin are partially left or substituted with other substituents, the interaction with the hydroxyl groups or other substituents. As a result, the clathration ability is significantly changed, so that it is expected that the type of guest molecule and its physical properties can be greatly changed. Therefore, various studies have been conducted on cyclodextrin derivatives in which such a hydroxyl group is substituted with another substituent.

For example, as an acetylated derivative of cyclodextrin, J. Carbohydr. Chem., 7 293-308 (1988).
, Carbohydr. Res., 187 203-221 (1989) and Takeo et al., And Carbohydr. Res., 192 366-369 (1989). The benzoylated derivative is described in the paper of Helv. Chim. Acta., 61 2190-2218 (1978).

[0005]

However, when the synthesis is carried out by the method described in the above-mentioned paper, there are problems such that decomposition products are generated due to the high reaction temperature and the inside of the reaction system is colored.

The present invention has been made to solve the above problems, and an object of the present invention is to provide a method capable of obtaining cyclodextrin acylation at a low temperature in a short time and in a high yield. And

[0007]

The present invention will be described in more detail below.

In the present invention, CD having n = 6 is α-
CD, with n = 7 is β-CD, with n = 8 is γ-C
Called D.

Specific reaction examples of the CD derivative of the present invention are shown below. <Example 1> Synthesis of 2,3-diacetyl-β-CD

[0010]

[Chemical 1]

Reaction [1] 6-tert-butyldimethylsilyl-β synthesized separately
-CD (6-t-BuDMSi-β-CD) is dehydrated TH
Dissolve in F, add triethylamine under nitrogen atmosphere and cool the system slightly. Acetyl cyanide dissolved in dehydrated THF was slowly added dropwise thereto, and the reaction was carried out at that temperature for 30 minutes and at room temperature for 2 hours. After completion of the reaction, the solution is concentrated under reduced pressure as it is, CH ₂ Cl ₂ is added to the residue, neutralized with an acid, washed with water, and CH ₂ Cl ₂ is distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography to obtain [A] (yield: about 90%).

Reaction [2] Next, the obtained [A] is dissolved in dehydrated dichloromethane and cooled to 0 to 5 ° C. under a nitrogen atmosphere. And BF ₃ · Et ₂
Slowly add O. After completion of dropping, the mixture is reacted at 0 to 5 ° C for 1 hour and at room temperature for 3 hours. After completion of the reaction, the mixture is added to ice-cooled water and the layers are separated. The organic layer is neutralized with a base, washed with water and dried. The dichloromethane layer was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography,
2,3-Diacetyl-β-CD [B] is obtained (yield: about 80%).

Example 2 Synthesis of 2,3,6-triacetyl-β-CD

[0014]

[Chemical 2]

Reaction [3] β-CD (n = 7) is dissolved in dehydrated DMF, triethylamine is added in a nitrogen atmosphere, and the system is cooled slightly. Acetyl cyanide dissolved in dehydrated DMF was slowly added dropwise thereto, and the reaction was carried out at that temperature for 30 minutes and at room temperature for 2 hours. After completion of the reaction, the solution is directly concentrated under reduced pressure at 40 ° C. or lower, and the residue is reprecipitated from a large amount of water. The precipitate is collected, washed well with water, dried, and purified by silica gel column chromatography to obtain 2,3,6-triacetyl-β-CD [C] (yield: about 95%).

The present invention is not limited to the above-mentioned examples, and other acyl compounds can be synthesized by simply changing the acetyl cyanide of Examples 1 and 2 to another acid cyanide. You can For example, in Example 1, when the acetyl cyanide in the reaction [1] was changed to benzoyl cyanide, 2,3-dibenzoyl-β-C was obtained.
Yield from D (6-t-BuDMSi-β-CD: about 7
5%) turns into pivaloyl cyanide, 2,3-
Dipivaloyl-β-CD (6-t-BuDMSi-β-
The yield from CD: about 70%) can be synthesized. Further, in Example 2, when the acetyl cyanide in the reaction [3] was changed to bromoacetyl cyanide, 2,3,6-tri (bromoacetyl) -β-CD (yield: about 90%) was converted to tributane. When changed to fluoroacetyl cyanide, 2,3,6-tri (trifluoroacetyl) -β-CD (yield: about 95
%) Can be synthesized.

As a method for synthesizing a substance having a Si group used for producing the cyclodextrin derivative of the present invention, J. Carbohydr. Chem., 7 293-308 (1988), Carbohydr.
Takeo et al., Res., 187 203-221 (1989) and Carbohydr.R.
es., 192 366-369 (1989) and the like.

[0018]

EFFECTS OF THE INVENTION By using an acid cyanide for acylating the hydroxyl group of cyclodextrin, it was possible to carry out the process in a short time and in a high yield. With respect to the reaction conditions as well, no decomposition products were generated and no coloration was observed when the temperature was from room temperature to room temperature. In addition, it is expected that various acylated derivatives can be synthesized by using various acid cyanides, the water solubility thereof will greatly change, and at the same time, the inclusion ability thereof will also greatly change.

Claims (1)

[Claims] 1. A method for producing a cyclodextrin derivative, which comprises reacting cyclodextrin or a cyclodextrin derivative with an acid cyanide to perform acylation.