JP2734295B2 - Cyclodextrin derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Cyclodextrin (hereinafter sometimes referred to as C
D) is a compound that has a hydrophobic cavity in the molecule and is hydrophilic on the outside and has a function similar to an oil-in-water micelle. Such a CD takes in a hydrophobic guest molecule according to its cavity diameter to form a complex in an aqueous solution, and depending on the preparation method, a solid inclusion compound can be isolated. Since the physicochemical properties of the guest molecule can be subtly changed by this stereoselective interaction, it can be expected to be effectively used for pharmaceuticals, and it is widely used in various fields and is being used. Compound.

In particular, in the case of a CD derivative partially leaving a hydroxyl group at the 2-, 3- or 6-position of CD, the inclusion ability is greatly changed by the interaction with the hydroxyl group. It can be expected that physical properties can be greatly changed.

For example, 6-methyl-CD in which the hydroxyl group at the 6-position is methylated is described in J. Carbohydr. Chem., 7 293-3.
08 (1988), a synthesis method using α-CD
In Carbohydr. Res., 187 203-221 (1989), a synthesis method using β- and γ-CD is described as a method different from the method using α-CD described above. It uses an agent, a catalyst and the like, and has a problem in cost.

Further, the above-mentioned Carbohydr. Res., 187 203-221
(1989) describes α, β-CD for 3-methyl-CD.
However, this method has a drawback that the process is complicated because a five-step reaction is required to obtain the desired product. Also, Carbohydr. Res., 2
00 481-485 (1990) describes a method using α, β, γ-CD,
Although methods for synthesizing 6-dimethyl-CD are also described, these methods have the drawback that the yield of the desired product is not sufficient.

Further, JP-A-3-137103 also discloses a method for synthesizing 3,6-dimethyl-CD in which the hydroxyl groups at the 3- and 6-positions are methylated.

Other methods for synthesizing intermediates are described in detail in Carbohydr. Res., 192 366-369 (1989) in addition to the above.

[0008]

However, a CD which partially leaves such a hydroxyl group at the 2,3- or 6-position.
The synthesis of the derivative has been very difficult due to the need to selectively react a specific hydroxyl group in the process.

An object of the present invention is to provide a CD derivative obtained by selectively methylating a specific hydroxyl group among hydroxyl groups of CD, and a method for producing the same.

It is another object of the present invention to provide a high-yield target product without using any expensive reagents and without producing side reactions in individual reactions. Another object of the present invention is to provide a method for synthesizing a CD derivative capable of selectively methylating a specific hydroxyl group.

[0011]

The present inventors have conducted intensive studies in view of the above-mentioned problems, and as a result, the above object of the present invention is represented by the following formula [I], [II] or [III]. It has been found that this is achieved by a cyclodextrin derivative.

[0012]

Embedded image

Another object of the present invention is to provide (6-O-tert-
After benzylating, allylating or pyranylating the hydroxyl groups at the 2- and 3-positions of (butyldimethylsilyl) cyclodextrin, the hydroxyl group at the 6-position of the cyclodextrin derivative obtained by desilylation is methylated and then hydrolyzed. , 6
-Methyl-cyclodextrin, (2,6-
A method for producing 3-methyl-cyclodextrin, wherein the hydroxyl group at position 3 of di-O-tert-butyldimethylsilyl) cyclodextrin is methylated and then desilylated, or (2,6-di-O-tert-). After benzylation, allylation or pyranylation of the hydroxyl group at the 3-position of (butyldimethylsilyl) cyclodextrin, the hydroxyl groups at the 2- and 6-positions of the cyclodextrin derivative obtained by desilylation are methylated and then hydrolyzed. And a method for producing 2,6-di-methyl-cyclodextrin.

Hereinafter, the present invention will be described more specifically.

In the present invention, CD having n of 6 is α-
CD, those with n = 7 are β-CD, those with n = 8 are γ-C
It is called D.

Hereinafter, specific reaction examples of the CD derivative of the present invention will be shown.

[0017]

Embedded image

The above reaction examples are specifically carried out by the following reactions. Synthesis of 6-methyl-β-CD Reaction [1] β-CD (n = 7) is dissolved in dehydrated pyridine and cooled to 0 to 5 ° C. under a nitrogen atmosphere. Then added dropwise ^t BDMSi · Cl were dissolved in dehydrated pyridine, After completion of the dropwise addition 0 to 5 ° C.
For 1 hour and at room temperature for 12 hours. After completion of the reaction, reprecipitation is performed from a large amount of water, and the precipitate is separated by filtration, washed well with water, and dried. Thereafter, purification was performed by silica gel column chromatography, and the obtained [A] was recrystallized three times from ethanol. (Yield: about 80%)

Reaction [2] [A] is dissolved in dehydrated DMF, and Na
Add H. Next, the system was cooled to 0 to 5 ° C., benzyl bromide was slowly added dropwise, and after completion of the addition, sodium iodide was added and the mixture was stirred at 0 to 5 ° C. for 6 hours and at room temperature for 48 hours. After completion of the reaction, methanol was added and the mixture was stirred.
1M-H ₂ SO ₄ was added to the filtrate in methylene chloride, washed sequentially with water, the organic phase is concentrated below under reduced pressure at 40 ° C. after drying. A small amount of DMF is added to the residue, reprecipitation is performed from methanol, and the precipitated precipitate is repeatedly recrystallized from ethanol to obtain [B]. (Yield: about 60%)

Reaction [3] [B] is dissolved in dehydrated THF, and 1M- (nC ₄
H _{9) 4} N ⁺ F ^- slowly added a THF solution of the completion of the dropwise addition shortly after each warmed, reacted under reflux for 24 hours. After completion of the reaction, the reaction solution is left to cool, and THF is distilled off under reduced pressure. The residue was dissolved in a small amount of ethanol, reprecipitated from a large amount of water, and purified by silica gel column chromatography [C].
Get. (Yield: about 65%)

Reaction [4] [C] is dissolved in dioxane, and Na
Add H. Then, the system is cooled to 0 to 5 ° C, and methyl iodide is slowly added dropwise under light shielding, and the mixture is reacted at 0 to 5 ° C for 2 hours and at room temperature for 12 hours. After completion of the reaction, methanol was added to the system, and the mixture was stirred. Then, the insoluble material was filtered. The filtrate was concentrated under reduced pressure at 40 ° C or lower, and the residue was recrystallized from methanol and purified by silica gel column chromatography to obtain [D]. .
(Yield: about 75%)

Reaction [5] [D] was dissolved in a 2/1 solution of ethanol / acetic acid, and 10%
After adding Pd / C as a catalyst, hydrogenation is performed (40
° C, 5 kg / cm ² ). When the hydrogen pressure no longer decreases, the reaction is terminated, Pd / C is filtered off, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain [E] 6-methyl-β-CD. . (Yield: about 90%)

Synthesis of 3-methyl-β-CD Reaction [6] β-CD (n = 7) is dissolved in dehydrated DMF, and imidazole is added at room temperature. Then under an argon atmosphere ^t BDM
Add Si · Cl and dissolve. Slowly heat the system
React at 90-100 ° C for 24 hours. After the reaction was allowed to cool, and the residue was distilled off under reduced pressure DMF was extracted from methylene chloride / water, the organic phase is 1M-H ₂ SO _4, dried after washed with water, saturated aqueous NaHCO _3. The organic phase is concentrated under reduced pressure, and the residue is recrystallized from a methylene chloride / methanol system and purified to obtain [F]. (Yield: about 65%)

Reaction [7] [G] is obtained in the same manner as in reaction [4] except that [F] is used instead of [C], and the residue is purified by silica gel chromatography without recrystallization. (Yield: about 70
%)

Reaction [8] [G] was dissolved in dehydrated THF, and 1M- (nC ₄
H _{9) 4} N ⁺ F ^- slowly added a THF solution of the reaction After completion of the dropwise little by little warmed under reflux for 36 hours. After completion of the reaction, the reaction solution is left to cool, and THF is distilled off under reduced pressure. The residue is purified by silica gel column chromatography to obtain [H] 3-methyl-β-CD. (Yield: about 80%)

Synthesis of 2,6-methyl-β-CD [9] [F] is dissolved in dioxane, and N 2 is added at room temperature under a nitrogen atmosphere.
Add aH. Then, the system was cooled to 0 to 5 ° C., and allyl bromide (R; CH ₂ ＣＨCH—CH ₂ —) was slowly added dropwise. After completion of the addition, sodium iodide was added.
Stir for 24 hours at room temperature. Added and stirred After completion of the reaction methanol, then the insoluble material was filtered off, 1M-H ₂ SO ₄ was added to the filtrate in methylene chloride, washed sequentially with water, the organic phase is concentrated below under reduced pressure at 40 ° C. After drying . The residue is purified by silica gel column chromatography to obtain [I]. (Yield: about 85%)

Reaction [10] [J] is obtained in the same manner as in reaction [8] except that [I] is used instead of [G]. (Yield: about 90%)

Reaction [11] Use [J] in place of [C] and DM in place of dioxane.
[K] is obtained in the same manner as in Reaction [4] except that F is used and the residue is purified by silica gel chromatography without recrystallization. (Yield: 75%)

Reaction [12] Perchloric acid and 5% Pd / C were added to a water / ethanol mixed solvent, and dissolved in ethanol at room temperature in the system [K].
Add. The system is then reacted at 70-80 ° C for 24 hours. After cooling, Pd / C is filtered off, and the filtrate is neutralized and concentrated while cooling. Methylene chloride is added to the residue, and the mixture is stirred. The insoluble material is filtered off. The filtrate is concentrated and purified by silica gel column chromatography to obtain [L] 2,6-methyl-β-CD.
(Yield: about 80%)

In the above reaction [1], when α-CD is used instead of β-CD, α-CD is replaced with dehydrated pyridine / dehydrated DM instead of dissolving β-CD in dehydrated pyridine.
The reaction can be carried out in the same manner as in the reaction [1], except that the compound [A] is dissolved in an F = 4/3 solution, and the obtained [A] is recrystallized from a methylene chloride / ethanol solution instead of recrystallizing with ethanol.

When γ-CD is used instead of β-CD, the same operation as in reaction [1] is performed except that [A] is recrystallized with a methylene chloride / methanol solution instead of recrystallizing with ethanol. Can do it.

[0032]

As described in detail above, the method of the present invention can provide a CD derivative obtained by selectively methylating a specific hydroxyl group among the hydroxyl groups of CD.

Further, according to the present invention, the desired product can be obtained in a high yield because no side reaction occurs in each reaction without using an expensive reagent, and the CD of any of α, β and γ can be obtained. A method for synthesizing a CD derivative capable of selectively methylating a specific hydroxyl group that can be synthesized can be provided.

Claims (4)

(57) [Claims] 1. The following formula [I], formula [II] or formula [III]
A cyclodextrin derivative represented by the formula: Embedded image 2. A cyclodextrin derivative 6 obtained by subjecting the 2- and 3-position hydroxyl groups of (6-O-tert-butyldimethylsilyl) cyclodextrin to benzylation, allylation or pyranylation, and then desilylation. A method for producing 6-methyl-cyclodextrin, comprising methylating a hydroxyl group at the position and hydrolyzing it. 3. A process for producing 3-methyl-cyclodextrin, which comprises methylating the hydroxyl group at the 3-position of (2,6-di-O-tert-butyldimethylsilyl) cyclodextrin and desilylating the methyl group. 4. A cyclodextrin derivative obtained by subjecting a hydroxyl group at the 3-position of (2,6-di-O-tert-butyldimethylsilyl) cyclodextrin to benzylation, allylation or pyranylation and then desilylation. A method for producing 2,6-di-methyl-cyclodextrin, which comprises methylating the hydroxyl groups at the 2- and 6-positions and then hydrolyzing the methyl groups.