JPH0543603A - (galactopyranosyl)cyclomaltheptaose, preparation thereof, and intermediate therefor - Google Patents

Abstract

PURPOSE:To obtain the title compound having both the clathrate function of cyclodextrins and affinity for a galactose receptor by selectively protecting the hydroxyl groups at the 4- and 6-positions in the pendant glucopyranosyl group and reversing the configuration of the 4-position hydroxyl group. CONSTITUTION:The hydroxyl groups at the 4- and 6-positions in the pendant glucopyranosyl group of (glucopyranosyl)cyclomaltheptaose of formula I are selectively protected and the configuration of the 4-position hydroxyl group is reversed to produce (galactopyranosyl)cyclomaltheptaose of formula II. In this process, a solution of an intermediate represented by formula III (wherein R is H, an acyl, or an alkyl, and R<4> is an alkyl or an aryl) in a specific solvent is stirred and the resulting precipitate is recovered by filtration and washed to obtain the compound of formula II as a white powder. This compound has the clathrate function of cyclodextrins and also has physiological functions such as affinity for a galactose receptor, so that it is useful in constructing a drug delivery system.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to (galactopyranosyl) cyclomaltoheptaose, a method for producing the same, and a production intermediate useful for producing the (galactopyranosyl) cyclomaltoheptaose.

[0002]

Cyclodextrin is an oligosaccharide having a clathrate function in which 6 to 8 glucoses are bound in a ring, and is used in the fields of cosmetics and foods. But,
Cyclodextrin itself is poorly soluble in water, and there is a problem that its use is limited. Therefore, as a cyclodextrin with improved water solubility, cyclodextrin is glucopyranosylated (glucopyranosyl) cyclomaltoheptaose (Shoichi Kobayashi, Keiji Minuma,
Suzuki Shigeo; Journal of the Japanese Society of Agricultural Chemistry, 51 691-698
(1977)) has been developed and is practically used for retaining aroma components and solubilizing fatty acids. However, no example is known in which cyclodextrin is galactopyranosylated.

[0003]

DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION AND MEANS FOR SOLVING THE PROBLEMS The present inventor has made earnest studies for the purpose of providing a novel cyclodextrin derivative containing a galactopyranosyl group, and a galactose derivative of cyclodextrin As a result, (galactopyranosyl) cyclomaltoheptaose was selected, and the present invention was completed. The compound is useful because it retains the inclusion function of cyclodextrin and has excellent water solubility. Further, the galactose introduced into the compound of the present invention is involved in various physiological actions such as differentiation and proliferation, cell identification, and reception and response of information. Therefore, the compound of the present invention has an affinity for the galactose receptor and the like. It is useful because it also has a physiological function. Further, according to the present invention, there is provided a method for efficiently producing the (galactopyranosyl) cyclomaltoheptaose and a production intermediate used in the production method.

The (galactopyranosyl) cyclomaltoheptaose of the present invention is a compound represented by the following formula (I).

[0005]

[Chemical 5]

An example of a method for producing the compound is shown in the following scheme. The method is characterized by selectively protecting the hydroxyl groups at the 4- and 6-positions of the branched glucopyranosyl group of (glucopyranosyl) cyclomaltoheptaose and inverting the configuration of the 4-position hydroxyl group. .. Compound 1 [6 used as a starting material in the production method
^A- O- (α-D-glucopyranosyl) -cyclomaltoheptaose] is a compound described in Shoichi Kobayashi, Keiji Minuma, Shigeo Suzuki; Journal of the Japanese Society of Agricultural Chemistry, 51 691-698 (1977). It can be produced by the method described in.

[0007]

[Chemical 6]

[0008]

[Chemical 7]

In compound 2, R is independently a hydrogen atom,
An acyl group or an alkyl group, R ¹ represents a hydrogen atom or an alkyl group, R ² represents an alkyl group, an aryl group which may have a substituent, or R ¹ together with-(CH ₂ ) _n- (n is It represents an integer of 4 to 6). In this specification,
The acyl group represents, for example, an aliphatic acyl group having 1 to 20 carbon atoms or an arylacyl group, and specifically, an aliphatic acyl group such as a formyl group, an acetyl group and a propionyl group, a trifluoroacetyl group, benzoyl. Examples of the aromatic acyl group such as a group and the like, and the alkyl group means, for example, an alkyl group having 1 to 10 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, n-butyl, sec- butyl group, refers to tert- butyl group, and the aryl group which may have a substituent, for example, a phenyl group,
Examples thereof include a pyridyl group, a chlorophenyl group and a tolyl group. In the compound 2, R is preferably an acetyl group, R ¹ and R ² are preferably a hydrogen atom and a phenyl group, respectively. Examples of the-(CH ₂ ) _n -group formed by R ¹ and R ² include a tetramethylene group, a pentamethylene group, and a hexamethylene group. Of these, a pentamethylene group in which n is 5 Is preferred.

In compound 3, R is independently a hydrogen atom,
It represents an acyl group or an alkyl group, and R ³ independently represents an alkyl group, a halogenated alkyl group, or an aryl group which may have a substituent. In the present specification, the halogenated alkyl group refers to, for example, a halogenated alkyl group having 1 to 2 carbon atoms, specifically, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group or the like.

In compound 4, R is independently a hydrogen atom,
It represents an acyl group or an alkyl group, and R ⁴ independently represents an alkyl group or an aryl group which may have a substituent.
These compounds are useful as intermediates for producing (galactopyranosyl) cyclomaltoheptaose of the present invention. In the above reaction scheme, reagents and reaction conditions that can be suitably used are described below. 1. 1 → 2 (first step) Solvent: aprotic polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, etc. Temperature: room temperature to 100 ° C. (50 to 70 ° C. is preferable) Time: 1 to 24 hours Reagent: d- Acid catalysts such as 10-camphorsulfonic acid and p-toluenesulfonic acid, and α, α-dimethoxytoluene,
Combination with acetals such as 2,2-dimethoxypropane and 1,1-dimethoxycyclohexane, or combination of ketones such as acetone, aldehydes such as benzaldehyde and acid catalysts such as sulfuric acid, and dehydrating agents such as anhydrous copper sulfate (part 1 2 steps) Temperature: -50 to 100 ° C Time: 1 to 48 hours Reagent: Combination of acid anhydride such as acetic anhydride, acid chloride such as benzoyl chloride and amines such as pyridine, or alkyl halide such as benzyl bromide And a combination of bases such as sodium hydride 2. 2 → 3 (first step) Solvent: water, methanol, ethanol, hydrous dioxane,
Tetrahydrofuran, acetic acid, etc. Temperature: 0 to 100 ° C. Time: 1 minute to 10 hours Reagent: Acid such as hydrochloric acid, sulfuric acid, toluenesulfonic acid, acetic acid, trifluoroacetic acid (second step) Temperature: −50 to 100 ° C. Time: 1 -48 hours Reagent: Combination of sulfonylating agents such as methanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride and pyridine, triethylamine and the like. 3 → 4 Solvent: aprotic polar solvent such as N, N-dimethylformamide, hexanemethylphosphoramide Temperature: 80 to 150 ° C. Time: 10 to 72 hours Reagent: benzoic acid, carboxylic acid such as acetic acid, alkali metal or ammonium Salt 4. 4 → (I) Removal of the protective group for hydroxyl group by a conventional method, for example, "Protect
ive Groups in Organic Synthesis "TW Green, Jo
By the method described in hn Wiley and Sons (1981)

[0012]

EXAMPLE A preferred embodiment of the present invention will be described below with reference to an example.
Aspects will be described in detail. The scope of the invention is
It is not limited. Example 1 Compound 1 → Compound 2 6¹-O- (2,3-di-O-acetyl-4,6-O-
Benzylidene-α-D-glucopyranosyl) -2¹, 2
², 2³, 2^Four, 2^Five, 2⁶, 2⁷, 3¹, 3 ²，
Three³, 3^Four, 3^Five, 3⁶, 3⁷, 6², 6³, 6^Four, 6
^Five, 6⁶, 6⁷-Icosa-O-acetylcyclomaltohe
Putaose (2) 6^A-O- (α-D-glycopyranosyl) -cyclomal
Toheptaose (1) (5.0 g, 3.9 mmol) was added to N, N-dimethylformamide.
Dissolve in (100 ml) and use α, α-dimethoxytoluene
(1 ml, 6.6 mmol) and d-10-camphorsulfo
Acid (1 g) was added. Reduce the pressure of this solution to approximately 20 mmHg.
Under heating, the mixture was heated and stirred at 60 to 70 ° C. for 6 hours. Furthermore, ice cooling
Lower pyridine (60 ml) and acetic anhydride (50 ml) were added.
And then at room temperature overnight, then heat to 100 ° C and stir for 2.5 hours.
Was done. The reaction mixture cooled to room temperature was cooled with ice water (500
ml), left overnight, and extracted with chloroform. Existence
Machine layer is saturated with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution
Wash sequentially with brine, dry over anhydrous sodium sulfate, and reduce.
The solvent was distilled off under reduced pressure. The obtained syrup is packed with silica gel.
Rum chromatography (chloroform-ethyl acetate-
2-propanol: 50: 50: 3 → 50: 50: 5)
Compound 2 (5.0 g, 53%) was obtained after purification by. [Α]^{twenty four} _D+ 107 ° (C 0.15, chloroform) IR (KBr); 2950, 1750, 1370, 1230, 1040cm^-1 NMR (CDCl₃, δ); 7.33-7.43 (m, 5H, Ph), 5.49 (s, 1
H, PhCH), 5.04-5.55 (m, 16H, 8xH-1,3), 4.92 (dd,
1H, J 4.0, 8.3Hz, H-2), 4.88 (dd, 1H, J 3.7, 10.0H
z, H-2), 4.86 (dd, 1H, J 3.7 10.1Hz, H-2), 4.83 (d
d, 1H, J 3.7, 8.9Hz, H-2), 4.78 (dd, 1H, J 4.0 9.5H
z, H-2), 4.76 (dd, 1H, J 4.0, 10.0Hz, H-2), 4.73
(dd, 1H, J 3.4, 9.8Hz, H-2), 4.69 (dd, 1H, J 3.6,
10.3Hz, H-2), 2.02-2.16 (m, 66H, 22xOAc) Elemental analysis: measured value; C, 51.29; H, 5.59 C₁₀₃H₁₃₄O₆₅Calculated as; C, 51.29; H, 5.60. Example 2 Compound 2 → Compound 3 6¹-O- (2,3-di-O-acetyl-4,6-di-
O-methanesulfonyl-α-D-glucopyranosyl)-
Two¹, 2², 2³, 2^Four, 2^Five, 2⁶, 2⁷, 3¹, 3
², 3³, 3^Four, 3^Five, 3⁶, 3⁷, 6², 6³，
6^Four, 6^Five, 6⁶, 6⁷-Icosa-O-acetylcyclo
Maltoheptaose (3) Compound 2 (2.60 g, 1.12 mmol) in 80% hydrous acetic acid
After that, the mixture was heated and stirred at 80 ° C. for 4 hours. Reduced solvent
Evaporate under pressure, add toluene and azeotrope the residual solvent.
Removed. Dissolve the residue in pyridine (50 ml) and cool with ice.
Methanesulfonyl chloride (2 ml) was added in small portions. reaction
The mixture was stirred overnight at room temperature, then poured into ice water and chlorolated.
Extracted with form. Extract the extract with 1M hydrochloric acid and saturated sodium bicarbonate.
Sequentially wash with thorium solution and saturated saline solution
After drying with sodium acidate, the solvent was distilled off under reduced pressure. Obtained
Silica gel column chromatography
Purified by roloform-methanol 98: 2 → 96: 4)
And a glassy compound 3 (2.35 g, 85%) was obtained.
It was [Α]^{twenty four} _D+ 117 ° (C 0.28, chloroform) IR (KBr); 2950, 1750, 1370, 1230, 1170, 1040cm^-1 NMR (CDCl₃, δ); 5.49 (t, 1H, J 9.27Hz, H-4), 5.04
-5.40 (m, 16H, 8xH-1,3), 4.68-4.90 (m, 8H, 8xH-2),
 3.10 (s, 3H, OMs), 3.08 (s, 3H, OMs), 2.00-2.14
(m, 66H, 22xOAc). Elemental analysis: measured value; C, 47.12; H, 5.49; S, 2.92. C₉₈H₁₃₄O₆₉S₂・ H₂Calculated as O; C, 47.12; H, 5.49;
 S, 2.57. Example 3 Compound 3 → Compound 4 6¹-O- (2,3-di-O-acetyl-4,6-di-
O-benzoyl) -2 ¹, 2², 2³, 2^Four, 2^Five, 2
⁶, 2⁷, 3¹, 3², 3³, 3^Four, 3^Five, 3 ⁶，
Three⁷, 6², 6³, 6^Four, 6^Five, 6⁶, 6⁷-Ikosa-
O-Acetylcyclomaltoheptaose (4) Compound 3 (1.0 g, 0.4 mmol) was added to N, N-dimethylformaldehyde.
Dissolve in muamide (40 ml) and add sodium benzoate (0.
7 g) and heated and stirred at 120-130 ° C. for 36 hours.
I did. The solvent was distilled off under reduced pressure, and dichloromethane was added to the residue.
-Add water to dissolve. Wash the separated organic layer with water a few times.
After that, dry over anhydrous sodium sulfate and concentrate under reduced pressure.
Contracted. Silica gel column chromatography of the concentrated residue
-(Benzene-tetrahydrofuran; 3: 1 → 2: 1)
The compound 4 (0.74 g, 73%) was obtained after purification. [Α]^{twenty four} _D+ 108 ° (C 0.24, chloroform) IR (KBr); 2950, 1750, 1275, 1240, 1040cm^-1 NMR (CDCl₃, δ); 7.30-7.60, 7.98-8.09 (m, 10H, 2xP
h) 5.89 (d, 1H, J 3.0Hz, H-4 (galactose)), 5.0
3-5.50 (m, 16H, 8xH-1.3), 4.70-4.90 (m, 8H, 8xH-2)
1.94-2.12 (m, 66H, 22xOAC) Elemental analysis: measured value; C, 52.33; H, 5.54 C₁₁₀H₁₃₈O₆₇C, 52.18; H, 5.49. Example 5 Compound 4 → Compound (I) 6¹-O- (α-D-galactopyranosyl) cyclomal
Toheptaose (5) -Compound 4 (300 mg, 0.12 mm
ol) to methanol (5 ml) -1M sodium methoxide
Dissolve in a methanol solution (0.2 ml) and stir at room temperature for 1 day.
I did. The precipitate formed is filtered and washed with methanol.
To give a white powder of compound (I) (145 mg, 93
%). m.p; 270 ℃ (decomposition) [α]^{twenty four} _D+ 150 ° (C 0.96, water) NMR (CDCl₃, δ); 5.00 (m, 7H, 7xH-1), 4.91 (d, 1H,
 J 3.7Hz, H-1) Elemental analysis: measured value; C, 41.81; H, 6.08 C₄₈H₈₀O₄₀・ 4H₂O Calculated as; C, 42.11; H, 6.48.

[0013]

INDUSTRIAL APPLICABILITY The (galactopyranosyl) cyclomaltoheptaose of the present invention has both the inclusion function of cyclodextrin and the affinity for the galactose receptor and is useful for the construction of a drug delivery system and the like. Moreover, the method of the present invention for producing (galactopyranosyl) cyclomaltoheptaose using (glucopyranosyl) cyclomaltoheptaose as a starting material is useful for chemically modifying a branched cyclodextrin and synthesizing a novel clathrate. is there.

Claims (5)

[Claims] 1. The following formula: Cyclomaltoheptaose represented by (galactopyranosyl). 2. The (glucopyranosyl) cyclomaltoheptaose branched glucopyranosyl group is selectively protected at the 4- and 6-position hydroxyl groups, and the configuration at the 4-position hydroxyl group is reversed. 1. The method for producing (galactopyranosyl) cyclomaltoheptaose according to 1. 3. The following formula: (In the formula, R independently represents a hydrogen atom, an acyl group, or an alkyl group, R ¹ represents a hydrogen atom or an alkyl group, R ² represents an alkyl group, an aryl group which may have a substituent, or R ¹ Together with-(CH ₂ ) _n- (n represents an integer of 4 to 6), the intermediate for producing (galactopyranosyl) cyclomaltoheptaose according to claim 1. 4. The following formula: (In the formula, R independently represents a hydrogen atom, an acyl group, or an alkyl group, and R ³ independently represents an alkyl group, a halogenated alkyl group, or an aryl group which may have a substituent), An intermediate for producing (galactopyranosyl) cyclomaltoheptaose according to claim 1. 5. The following formula: (Wherein R independently represents a hydrogen atom, an acyl group, or an alkyl group, and R ⁴ independently represents an alkyl group or an aryl group which may have a substituent). Galactopyranosyl) cyclomaltoheptaose intermediate.