JPH06239903A - Cyclodextrin derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a cyclodextrin derivative which is prepared by carbonylating the 3-hydroxy group of 2-hydroxy-protected (6-O-t-butyldimethylsilyl)cyclodextrin followed by desilylation, thus has largely improved clathration capacity and enables extension of the kinds of guest molecules. CONSTITUTION:beta-Cyclodextrin is dissolved in anhydrous pyridine and cooled down to 0 to 5 deg.C in a nitrogen atmosphere, and t-butyldimethylsilyl chloride is added dropwise to the solution to give 2-hydroxy-protected (6-O-t- butyldimethylsilyl)-cyclodextrin or (2,6-di-O-t-butyldimethylsilyl)cyclodextrin, which is carbonylated at its 3-hydroxy group by oxidation in a polar aprotic solvent such as dimethyl sulfoxide using dicyclohexylcarbodiimide as an electrophilicity-activating agent, then desilylated to give the novel objective cyclodextrin derivative of formula I or formula II ((n) is 6 to 8).

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 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 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 conducted on cyclodextrin derivatives in which such a hydroxyl group is substituted with other substituents, but none of those in which any of the hydroxyl groups is substituted with a carbonyl group has been reported.

[0005]

It is believed that cyclodextrin actually encloses various substances on the side of the hydroxyl group at the 2- or 3-position, which has a larger cavity diameter than the side of the hydroxyl group at the 6-position. There are no reports on compounds in which these are substituted with carbonyl groups, particularly compounds in which all of the 2-position hydroxyl groups or all of the 3-position hydroxyl groups are replaced with carbonyl groups. Therefore, in the case of such a compound, since the interaction with the hydroxyl group or the carbonyl group is further changed, 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 the hydroxyl groups at the 2-position or the 3-position are substituted with carbonyl groups, and a method for producing these derivatives.

[0007]

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

[0008]

[Chemical 2]

Further, the above object of the present invention is (1) (6-O-tert-butyldimethylsilyl) cyclodextrin or (2,6-di-O-tert) in which a hydroxyl group at the 2-position is protected by a protecting group. -Butyldimethylsilyl) cyclodextrin 3-position hydroxyl group is carbonylated and then desilylated, (2) The carbonylation described in (1) above is polar aprotic. The method for producing a cyclodextrin derivative according to (1) above, which comprises oxidizing a hydroxyl group using a non-electron active reagent in a solvent, (3) cyclodextrin in which the hydroxyl groups at the 3- and 6-positions are protected with a protective group Or 3
Position-protected with a protecting group (6-O-tert-butyldimethylsilyl) cyclodextrin, the method for producing a cyclodextrin derivative, characterized by removing the protecting group after carbonylating the 2-position hydroxyl group, or (4) The method for producing a cyclodextrin derivative according to the above (3), wherein the carbonylation according to the above (3) is performed by oxidizing a hydroxyl group with a non-electron active reagent in a polar aprotic solvent. .

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.

In the present invention, the polar aprotic solvent used in the carbonylation of the hydroxyl group is preferably dimethyl sulfoxide (hereinafter abbreviated as DMSO), and the electrophilic activating reagent is preferably dicyclohexylcarbodiimide ( Hereinafter, abbreviated as DCC), acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, trifluoroacetic anhydride, oxalyl chloride and the like are used.

Specific reaction examples of the cyclodextrin derivative of the present invention represented by the formula [I] are shown below. However, in the following cases, cyclodextrin is abbreviated as CD.

[0014]

[Chemical 3]

The above reaction is specifically carried out by the following method. 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 was added dropwise, and after completion of the addition, 1 at 0-5 ° C.
Stir for 12 hours at room temperature. After completion of the reaction, reprecipitation is carried out from a large amount of water, the precipitate is filtered off, washed well with water and dried.
Then, the product is purified by silica gel column chromatography, and the obtained [A] is recrystallized from ethanol three times. (Yield: about 80%)

Reaction [2] [A] was dissolved in dehydrated DMF, and BaO, B was added in a nitrogen atmosphere.
_{a (OH) 2 · 8H 2} O was added, reacted at room temperature for 1 hour. Benzyl bromide is added dropwise to the system at room temperature, and after completion of the addition, sodium iodide is added and reacted for 24 hours. After completion of the reaction, methanol was added and the precipitate was filtered off, and the filtrate was CH ₂ Cl ₂
Was added, 1M-H ₂ SO _4, washed sequentially with water, the organic layer is concentrated after drying under reduced pressure. Add a small amount of ethanol to the residue,
Reprecipitate from a large amount of water. The precipitate is dried and then purified by silica gel column chromatography to obtain [B].
(Yield: about 70%)

Reaction [3]Method-I Dissolve [B] in DMSO and then at room temperature DCC
Chlorhexylcarbodiimide) is added. Furthermore the system
While keeping the temperature at 20 to 30 ° C, add phosphoric anhydride little by little.
Ku. After adding all, stir at that temperature for 24 hours and filter the precipitate.
After CH₂ Cl ₂ Add Na₂ CO₃ Neutralize with aqueous solution
It CH₂ Cl₂ After extraction with, the organic layer is washed well with water,
After drying, concentrate under reduced pressure and chromatograph the residue on a silica gel column.
Purify by Raffy to obtain [C]. (Yield: about 60%)

Method-II [B] is dissolved in DMSO and acetic anhydride is added.
The system is then heated to 40-50 ° C and stirred for 4 hours. After the reaction is complete, CH ₂ Cl ₂ is added, followed by a large amount of water. The organic layer is separated, neutralized with an aqueous Na ₂ CO ₃ solution, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain [C]. (Yield: about 65%)

[0019]Method-III Dissolve [B] in DMF / DMSO mixed solvent
Add phosphorus oxide, heat slowly and stir at 50-60 ° C for 3 hours.
Stir. After the reaction was completed, the precipitate was filtered off and the filtrate was CH ₂ Cl₂ 
Was added, and then a large amount of water was added, the organic layer was separated, and Na was added.
₂ CO₃ Neutralize with aqueous solution, wash with water, dry and concentrate under reduced pressure.
It The residue was subjected to silica gel column chromatography.
Purify to obtain [C]. (Yield: about 65%)

Method-IV [B] is dissolved in dehydrated DMSO and a small amount of triethylamine is added at room temperature. Then, a DMSO solution of sulfur trioxide-pyridine complex is slowly added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 6 hours, and after the reaction is completed, the sulfur trioxide-pyridine complex is used as a salt, and what is formed as a precipitate is filtered off. The filtrate is concentrated under reduced pressure at 40 ° C. or lower, and the residue is purified by silica gel column chromatography to obtain [C]. (Yield: about 60%)

Method-V The dehydrated DMSO / dichloromethane mixed solvent was cooled to about -60 ° C under a nitrogen atmosphere, and a solution of trifluoroacetic anhydride in dichloromethane was added to the system. After stirring for about 30 minutes, the dichloromethane solution of [B] is added dropwise, and the mixture is stirred at -60 ° C for about 3 hours. After that, triethylamine is added, and after stirring for about 30 minutes, the system temperature is slowly returned to room temperature. Next, water was added to the system to separate the organic layer. The organic layer was concentrated under reduced pressure at 40 ° C or lower, and the residue was purified by silica gel column chromatography, [C].
To get (Yield: about 55%)

Method-VI [C] is obtained in the same manner as in Method-V except that methanol is used in place of triethylamine in the above Method-V. (Yield: about 65%)

Reaction [4] [C] was dissolved in THF, and 1M- (n-C ₄ H was added at room temperature.
_{9) 4} N ⁺ F ^- THF was added and the reaction After completion of the dropwise slowly warmed under reflux for 24 hours. After completion of reaction THF
Is distilled off under reduced pressure, the residue is extracted with CH ₂ Cl ₂ / water system, the organic layer is dried and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain [D]. (Yield: about 85%)

Reaction [5] [D] is dissolved in acetic acid and hydrogenation is carried out after adding 10% Pd / C as a catalyst (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, and the residue is reprecipitated from a large amount of acetone. The precipitate is collected and washed well with acetone to obtain [E]. (Yield: about 90%)

Reaction [6] β-CD (n = 7) was dissolved in dehydrated DMF, and the mixture was allowed to stand at room temperature.
Add Dazole. Then under argon atmosphere^tBD
Add MSiCl and dissolve. Slowly heat the system
And react at 90-100 ° C for 24 hours. Allow to cool after completion of reaction
Then, DMF was distilled off under reduced pressure, and the residue was CH.₂ Cl₂ / Water system
Extracted, CH₂ Cl₂ Layer is 1M-H₂ SO _Four , Water, N
aHCO₃ Wash with saturated aqueous solution and dry. CH₂ Cl₂ 
Is concentrated under reduced pressure and the residue is CH₂ Cl₂ / Methanol system
[F] is obtained by recrystallization and purification. (Yield: about 65
%)

Reaction [7] [G] is obtained in the same manner as in each of methods [I] to [VI] of reaction [3] except that [F] is used instead of [B]. (For method [I], yield: about 70%)

Reaction [8] [G] was dissolved in THF, and 1M- (n-C ₄ H) was added at room temperature.
_{9) 4} N ⁺ F ^- THF was added and the reaction After completion of the dropwise slowly warmed under reflux for 24 hours. After completion of the reaction, the precipitate is filtered off, the precipitate is dissolved in water and reprecipitated from a large amount of acetone. The precipitate is often washed with acetone and dried to obtain [E]. (Yield: about 75%)

Next, specific reaction examples of the cyclodextrin derivative of the present invention represented by the formula [II] will be shown.

[0029]

[Chemical 4]

The above reaction is specifically carried out by the following method. 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 was added dropwise, and after completion of the addition, 1 at 0-5 ° C.
Stir for 12 hours at room temperature. After completion of the reaction, reprecipitation is carried out from a large amount of water, the precipitate is filtered off, washed well with water and dried.
Then, the product is purified by silica gel column chromatography, and the obtained [A] is recrystallized from ethanol three times. (Yield: about 80%)

Reaction [2] [A] was dissolved in dehydrated DMF, and BaO and B were added in a nitrogen atmosphere.
_{a (OH) 2 · 8H 2} O was added, reacted at room temperature for 1 hour. Benzyl bromide is added dropwise to the system at room temperature, and after completion of the addition, sodium iodide is added and reacted for 24 hours. After completion of the reaction, methanol was added, the precipitate was filtered off, and CH ₂ Cl was added to the filtrate.
₂ was added, 1M-H ₂ SO _4, washed sequentially with water, the organic layer is concentrated after drying under reduced pressure. Add a small amount of ethanol to the residue and reprecipitate from a large amount of water. The precipitate is dried and then purified by silica gel column chromatography to obtain [B]. (Yield: about 70%)

Reaction [3] [B] was dissolved in THF, and 1M- (n-C ₄ H) was added at room temperature.
_{9) 4} N ⁺ F ^- THF was added and the reaction After completion of the dropwise slowly warmed under reflux for 24 hours. After completion of reaction THF
Is distilled off under reduced pressure, the residue is extracted with a CH ₂ Cl ₂ / water system, the organic layer is dried and then concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain [C]. (Yield: about 85%)

Reaction [4] [C] is dissolved in dehydrated pyridine and acetic anhydride is added at room temperature. After the addition, the mixture is stirred at 90 to 100 ° C for 6 hours, after completion of the reaction, pyridine is distilled off under reduced pressure, and the residue is poured into a large amount of ice-cooled water. [D] is obtained by collecting the deposited precipitates and purifying by silica gel column chromatography. (R ₂ ; CH ₃ CO
-, Yield: about 90%)

Reaction [5] [D] was dissolved in ethanol / acetic acid = 2/1 to obtain 10% Pd.
/ C as a catalyst and then hydrogenation (40 ℃, 5kg
/ 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, and the residue is purified by silica gel column chromatography to obtain [E]. (Yield: about 90%)

Reaction [6]Method-I Dissolve [E] in DMSO and then at room temperature with DCC
Chlorhexylcarbodiimide) is added. Furthermore the system
While keeping the temperature at 20 to 30 ° C, add phosphoric anhydride little by little.
Ku. After adding all, stir at that temperature for 24 hours and filter the precipitate.
After CH₂ Cl ₂ Add Na₂ CO₃ Neutralize with aqueous solution
It CH₂ Cl₂ After extraction with, the organic layer is washed well with water and dried.
After drying, concentrate under reduced pressure and chromatograph the residue on a silica gel column.
Purify by Raffy to obtain [F]. (Yield: about 55%)

Method-II [E] is dissolved in DMSO and then acetic anhydride is added.
The system is then heated to 40-50 ° C and stirred for 4 hours. After the reaction is complete, CH ₂ Cl ₂ is added, followed by a large amount of water. The organic layer is separated, neutralized with an aqueous Na ₂ CO ₃ solution, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain [F]. (Yield: about 60%)

Method-III [E] is dissolved in a DMF / DMSO mixed solvent, phosphorus pentoxide is added, and the mixture is slowly heated and stirred at 50-60 ° C for 3 hours. After the reaction was completed, the precipitate was filtered off, CH ₂ Cl ₂ was added to the filtrate, and then a large amount of water was added to separate the organic layer, and Na ₂ C was added.
Neutralize with O ₃ aqueous solution, wash with water, dry and concentrate under reduced pressure. The residue is purified by silica gel column chromatography to obtain [F]. (Yield: about 65%)

Method-IV [E] is dissolved in dehydrated DMSO and a small amount of triethylamine is added at room temperature. Then, a DMSO solution of sulfur trioxide-pyridine complex is slowly added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 6 hours, and after the reaction is completed, the sulfur trioxide-pyridine complex is used as a salt, and what is formed as a precipitate is filtered off. The filtrate is concentrated under reduced pressure at 40 ° C. or lower, and the residue is purified by silica gel column chromatography to obtain [F]. (Yield: about 60%)

Method-V The dehydrated DMSO / dichloromethane mixed solvent was cooled to about -60 ° C under a nitrogen atmosphere, and a solution of trifluoroacetic anhydride in dichloromethane was added to the system. After stirring for about 30 minutes, a solution of [E] in dichloromethane was added dropwise, and the mixture was stirred at -60 ° C for about 3 hours. After that, triethylamine is added, and after stirring for about 30 minutes, the system temperature is slowly returned to room temperature. Next, water is added to the system to separate the organic layer. The organic layer is concentrated under reduced pressure at 40 ° C or lower, and the residue is purified by silica gel column chromatography, [F].
To get (Yield: about 55%)

Method-VI [F] is obtained in the same manner as in Method-V except that methanol is used instead of triethylamine in the above Method-V. (Yield: about 65%)

Reaction [7] [F] is dissolved in a methanol solution of NaOH and stirred at room temperature. After 3 hours, the reaction is stopped, the resulting precipitate is filtered off, washed thoroughly with methanol, dissolved in a small amount of pyridine, and reprecipitated from a large amount of acetone. [G] is obtained by collecting the precipitates and drying under reduced pressure. (Yield: about 80%)

Reaction [8] [B] is dissolved in dehydrated CH ₂ Cl ₂ , pyridine is added as a catalyst, and the mixture is cooled to 0 to 5 ° C. under a nitrogen atmosphere. Then, benzoyl chloride dissolved in CH ₂ Cl ₂ is slowly added dropwise to the system, and after completion of the addition, the mixture is stirred at room temperature for 2 hours. After completion of the reaction, the mixture is poured into ice-cooled water, the organic layer is separated, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography to obtain [H]. (Yield: about 60%)

Reaction [9] [I] is obtained in the same manner as in Reaction [5] except that [H] is used instead of [D]. (Yield: about 85%)

Reaction [10] [J] is obtained in the same manner as in each of the methods [I] to [VI] of reaction [6] except that [I] is used instead of [E]. (For method [I], yield: about 60%)

Reaction [11] [K] is obtained in the same manner as Reaction [3] except that [J] is used instead of [B]. (Yield: about 90%)

Reaction [12] [G] is obtained in the same manner as in Reaction [7] except that [K] is used instead of [F]. (Yield: about 70%)

For the synthesis of intermediates used in the preparation of the cyclodextrin derivatives of the present invention, see J. Carbohyd.
r. Chem., 7 293-308 (1988); Carbohydr. Res., 187 2
03-221 (1989); Carbohydr. Res., 192 366-369 (198
It is described in detail in the papers such as 9).

[0048]

INDUSTRIAL APPLICABILITY The production method of the present invention can provide a cyclodextrin derivative in which all hydroxyl groups at the 2-position or 3-position are substituted with carbonyl groups.

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. In addition, the hydroxyl group becomes a carbonyl group, which significantly changes the water solubility.
It is expected that the inclusion ability of will change greatly.

Claims (9)

[Claims] 1. A cyclodextrin derivative represented by the following formula [I] or formula [II]. [Chemical 1] 2. A hydroxyl group at the 2-position is protected by a protecting group (6
-O-tert-butyldimethylsilyl) cyclodextrin or (2,6-di-O-tert-butyldimethylsilyl) cyclodextrin is characterized in that the 3-position hydroxyl group is carbonylated and then desilylated. Method for producing dextrin derivative. 3. The method for producing a cyclodextrin derivative according to claim 2, wherein the carbonylation according to claim 2 is performed by oxidizing a hydroxyl group using an electrophilic activating reagent in a polar aprotic solvent. 4. The method for producing a cyclodextrin derivative according to claim 3, wherein dimethyl sulfoxide is used as the polar aprotic solvent. 5. The cyclodextrin derivative according to claim 3, wherein a substance selected from dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, trifluoroacetic anhydride, and oxalyl chloride is used as the electrophilic activating reagent. Manufacturing method. 6. A cyclodextrin having hydroxyl groups at the 3- and 6-positions protected with a protecting group, or a hydroxyl group at 2-positions of (6-O-tert-butyldimethylsilyl) cyclodextrin protected with a 3-position protecting group. A method for producing a cyclodextrin derivative, which comprises carbonylating and then removing a protecting group. 7. The method for producing a cyclodextrin derivative according to claim 6, wherein the carbonylation according to claim 6 is performed by oxidizing a hydroxyl group using an electrophilic activating reagent in a polar aprotic solvent. 8. The method for producing a cyclodextrin derivative according to claim 7, wherein dimethyl sulfoxide is used as the polar aprotic solvent. 9. The cyclodextrin derivative according to claim 7, wherein a substance selected from dicyclohexylcarbodiimide, acetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, trifluoroacetic anhydride and oxalyl chloride is used as the electrophilic activating reagent. Manufacturing method.