JPH05255369A - Ether type 1,3-glycero-based oligoglycolipid - Google Patents

Abstract

PURPOSE:To obtain a new compound, capable of forming an endoplasmic reticulum of several nm to mum size and suitable as a drug carrier, a monomolecular film, etc. CONSTITUTION:The objective compound of formula I (R is oligisaccharide residue having glucose, galactose and mannose as a constituent saccharide unit and reducing terminal, e.g. 1,3-di-0-dodecyl-2-0-(beta-D-cellobiosyl)glycerol. Furthermore, the compound of formula I is obtained by reacting, e.g. trichloroacetimidate of an acetyloligosaccharide with 1,3-di-O-dodecyl-3-propanol of formula II in the presence of a Lewis acid catalyst.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel ether type 1,
It relates to a 3-glycero oligoglycolipid. This is used as an emulsifier, stabilizer, dispersant, solubilizer, admixture, wetting agent, penetrant, viscosity modifier for foods, cosmetics, dyes, etc., or as a fiber, plastic, metal, ceramics, glass, etc. As a surface modifier of
It is suitable as a biocompatible material as a drug carrier material for enclosing a water-soluble drug in the endoplasmic reticulum, or as an organic thin film material or a semiconductor-related organic substrate material.

[0002]

Conventionally, polyoxyethylene-based surfactants and sugar esters have been known as nonionic surfactants used in the industrial fields of foods, cosmetics, dyes, etc. The agent has a drawback in that it has a strong irritation to the skin and mucous membranes and crystallizes at a temperature higher than the cloud point, so that the solubilizing ability at a high temperature decreases. Further, the sugar ester is acidic and easily hydrolyzed, and it is a mixture of isomers / analogs having different positions / numbers of hydroxyl groups to be esterified, and it is difficult to produce the sugar ester as a single compound with high purity. It has the drawback. In addition, natural oligoglycolipids have multiple structurally similar oligosaccharide hydrophilic moieties that exist in a mixed state, and also have fatty acid moieties of various lengths in the hydrophobic diglyceride moiety. It is very difficult to purify and obtain a highly pure product. On the other hand, glucose is a hydrophilic group,
It is known to produce glyceroglycolipids having 1,2-diacylglyceride as a hydrophobic group (Chem. Phys. Lipids).
Vol. 113 (1987)). However, the glycolipid having a monosaccharide as a hydrophilic part thus obtained has a drawback that the lamellar liquid crystal phase has low temperature stability because it undergoes a phase transition from the lamellar liquid crystal phase to the hexagonal bi-liquid crystal phase at high temperature. There is. Further, as for the hydrophobic part, since 1,2-diacylglyceride has an asymmetric point, it is necessary to produce an optically active hydrophobic group from mannitol through several steps of reaction in order to obtain a glycolipid having a single structure. In addition, the ester bond is chemically unstable because it is easily hydrolyzed under alkaline conditions, and the yield of the deprotection reaction under the basic conditions at the final stage is as low as 40 to 50%. is doing.

[0003]

DISCLOSURE OF THE INVENTION The present invention has the characteristics of amphipathic properties equivalent to those of natural products, and can be produced in a short step as a high-purity single compound from various oligosaccharides including disaccharides and above. The purpose of the invention is to obtain an oligoglycolipid that is chemically stable in a wide pH range and has excellent temperature stability in a lamellar liquid crystal phase.

[0004]

That is, the present invention provides a general formula

[Chemical 2] (R is an oligosaccharide residue having glucose, galactose or mannose as a constituent sugar unit and having a reducing end), which provides an ether type 1,3-glycero oligoglycolipid. The compounds represented by the general formula (1) are all novel compounds which have not been published in the literature.
It can be produced from an oligosaccharide having glucose, galactose, mannose or the like as a constituent sugar residue and having a reducing end, by the following 5-step method. First, the oligosaccharide is acetylated with acetic anhydride in the presence of a base. As a solvent for the acetylation reaction, an ether solvent such as THF and diethyl ether, pyridine and the like can be used, and pyridine is suitable. As a base for this reaction, an organic base such as pyridine or triethylamine is suitable. N, N-dimethylaminopyridine can also be used as a catalyst. Next, hydrazine acetate is allowed to act to selectively deprotect the acetyl group at the reducing terminal position. As a solvent for this reaction, acetonitrile, DMF, THF, ether and the like can be used, but DMF gives good results. A suitable reaction temperature is 50 ° C. Reaction time is 2
Time is enough. Then, using this as a base catalyst,
By reacting with trichloroacetonitrile, trichloroacetimidate of acetyl oligosaccharide in which the reducing terminal position is selectively activated can be obtained in high yield. As the reaction solvent, halogen-based solvents such as methylene chloride, 1,2-dichloroethane and chloroform are suitable. As the base, sodium hydride, DBU, cesium carbonate can be used. When the reaction is carried out under the condition of stirring at room temperature for 2 hours or more, α-form trichloroacetimidate is selectively obtained. One of these compounds
H-NMR spectrum (in deuterated chloroform, 25 ° C)
Since a doublet signal (spin-spin coupling constant 3.4-4.0 Hz) is shown at δ value of 6.4-6.6 ppm, it can be confirmed that these compounds are α-form imidates. Next, the α-form trichloroacetimidate was added to the general formula in the presence of a Lewis acid catalyst.

[Chemical 3] By reacting with 1,3-di-O-dodecyl-3-propanol represented by, the β-form glycosyl form can be selectively obtained. As the reaction solvent, halogen solvents such as chloroform, methylene chloride and 1,2-dichloroethane, acetonitrile and nitromethane can be used, but methylene chloride is suitable. As the Lewis acid catalyst for this reaction, trimethylsilyl trifluoromethanesulfonate or boron trifluoride / ether complex can be used. The Lewis acid catalyst is used in an amount of 1.5 equivalents or more based on trichloroacetimide, which gives good results. Reaction temperature is -25 ° C
The above is appropriate. A reaction time of 45 minutes or more is sufficient. At this time, stirring under the coexistence of the molecular sieve 4A gives good results. Finally, the glycosyl form is treated with sodium or potassium alcoholate,
By recrystallizing the powder obtained by cooling / filtering or distilling off the solvent, an ether type 1,3-glycero oligoglycolipid represented by the general formula (〓) is obtained as a white powder with a yield of 70 to 95%. Be done. A suitable reaction temperature is 0 ° C. or higher. The reaction solvent is an alcohol solvent such as methanol or ethanol, or diethyl ether or T
A mixed solvent of an ether solvent such as HF and an alcohol solvent is suitable. As the recrystallization solvent, an alcohol solvent such as methanol or ethanol, acetone, pyridine, THF, or a mixed solvent thereof can be used. The compound of the present invention has an infrared absorption spectrum of
It exhibits characteristic absorption derived from a hydroxyl group at 3500 to 3300 cm -1, and has a δ value of 0.5-0.8 in 1 H-NMR.
ppm, 0.9-1.4 ppm, 2.9-4.4 ppm position, hydrogen of methyl group of long-chain alkyl group, hydrogen of methylene group of long-chain alkyl group, glycerol part and its adjacent methylene and oligosaccharide moieties The signals respectively assigned to the hydrogens of the above can be observed, and the products can be identified by these.

[0005]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Reference Example 1 Method for producing trideca-O-acetyl-α-D-cellotetraosyl trichloroacetimidate 200 mg (0.30 mmol) of D-cellotetraose and 5 mg of N, N-dimethylaminopyridine were dissolved in 4.0 ml of pyridine, 1.02 g (51 mmol) of acetic anhydride was added with stirring at 0 ° C. After stirring this at room temperature overnight, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 40 (volume ratio)) to prepare tetradeca-O-acetyl-D-cello. Tetraose 380 mg (yield 100%) was obtained as a white powder. 380 mg of this compound (0.
(30 mmol) was dissolved in 14 ml of DMF, 41 mg (0.45 mmol) of hydrazine acetate was added, and the mixture was heated and stirred at 50 ° C. for 2 hours. After the solution was cooled to room temperature, ethyl acetate 30
It was diluted with 30 ml and washed 7 times with 30 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 40 (volume ratio)) to obtain 345 mg of 1-hydroxy-D-cellotetraose tridecaacetate (yield 96%) as a white powder. This compound (310 mg, 0.256 mmol) was dissolved in methylene chloride (7.0 ml) and trichloroacetonitrile (0.7 ml) was added thereto.
Then 12 ml (0.50 mmol) of sodium hydride was added.
After stirring at room temperature for 5 hours, the mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / acetone = 4 (volume ratio)) to obtain 335 mg of the desired compound (yield 96%) as a white powder. The 1 H-NMR spectrum (25 ° C. in deuterated chloroform) of this product showed a singlet signal at δ value of 8.63 ppm and a doublet signal at 6.47 ppm (spin-spin coupling constant, 3.96 Hz). ..

[0006]

Reference Example 2 Instead of cellotetraose in Reference Example 1, the corresponding oligosaccharide was used, and the following compound was obtained by the same procedure. The signal characteristic of α-trichloroacetimidate of 1 H-NMR spectrum (in deuterated chloroform, 25 ° C.) is shown by δ value. Tetra-O-acetyl-α-D-glucosyl trichloroacetimidate 8.58ppm (s), 6.47ppm (d, J = 3.45Hz) Hepta-O-acetyl-α-D-cellobiosyl trichloroacetimidate 8.60ppm (s) ), 6.48ppm (d, J = 3.63Hz) Deca-O-acetyl-α-D-cellotriosyl trichloroacetimidate 8.71ppm (s), 6.51ppm (d, J = 3.63Hz) Nonadeca-O-acetyl-α -D-cellohexaosyl
Trichloroacetimidate 8.74ppm (s), 6.55ppm (d, J = 3.63Hz) Hepta-O-acetyl-α-D-maltosyl trichloroacetimidate 8.70ppm (s), 6.56ppm (d, J = 3.62Hz) ) Trideca-O-acetyl-α-D-maltotetraosyl trichloroacetimidate 8.70ppm (s), 6.56ppm (d, J = 3.62Hz) Nonadeca-O-acetyl-α-D-maltohexaosyl trichloro Acetoimidate 8.72ppm (s), 6.55ppm (d, J = 3.62Hz)

[0007]

Example 1 1,3-di-O-dodecyl-2-O- (β-
Method for producing D-cellobiosyl) -glycerol 100 mg of the powder of the molecular sieve 4A in a reaction flask is heated and dried under reduced pressure and cooled to an argon atmosphere. To this was added a solution of 107 mg (0.25 mmol) of 1,3-di-O-dodecyl-2-propanol in methylene chloride (3.0 ml).
Was added. After stirring for 30 minutes, hepta-O-acetyl-α-D-cellobiosyltrichloroacetimidate 1
95 mg (0.25 mmol) methylene chloride solution (2.5 ml) was added. A solution of trimethylsilyl trifluoromethanesulfonate (120 mg, 0.54 mmol) in methylene chloride (0.5 ml) was added while the reaction flask was cooled to 0 ° C, and the mixture was stirred at 0 ° C for 90 minutes. After adding 50 mg (0.50 mmol) of triethylamine in methylene chloride solution (1.0 ml) at 0 ° C., the solution was diluted with 30 ml of ethyl acetate at room temperature. The suspension was filtered over Celite, and the filtrate was washed once with 30 ml of saturated aqueous sodium hydrogen carbonate solution and then with 30 ml of saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / acetone = 9 (volume ratio)) to give 1,3-di-O-dodecyl-2-O- (hepta-O-acetyl-β- as white powder. 236 mg (yield 90%) of D-cellobiosyl) -glycerol was obtained.
After dissolving 236 mg (0.225 mmol) of this compound in 5.0 ml of methanol, 0.5 ml of 1.0 N sodium methoxide in methanol was added. After stirring at room temperature for 2 hours, 1 at 3 ℃
A white precipitate formed upon standing overnight. This was separated by filtration, washed with a small amount of methanol, and this white powder was recrystallized twice from methanol and dried to obtain 144 mg (yield 85%) of the target compound as a white powder. Figure 1
A polarizing microscope photograph of a 30 wt% aqueous solution of this product is shown in FIG. FIG. 2 shows the differential scanning calorimetry curve of a 1 wt% aqueous solution of this product. The hydrated crystal-lamella liquid crystal phase transition temperature Tm of this product was 4
It was 6 ° C. The infrared absorption spectrum of this product is 3600
Absorption was observed at -3300 cm-1,2930 cm-1,1625 cm-1,114-1000 cm-1. FIG. 3 shows the 1 H-NMR spectrum (deuterated chloroform / deuterated methanol = 1, 25 ° C.).

[0008]

Example 2 1,3-di-O-dodecyl-2-O- (β-
Method for producing D-cellotetraosyl) -glycerol 160 mg of molecular sieve 4A powder in a reaction flask
Is dried under reduced pressure by heating and drying to make an argon atmosphere.
To this, 59 g of 1,3-di-O-dodecyl-2-propanol
A solution of g (0.14 mmol) in methylene chloride (2.0 ml) was added.
After stirring for 30 minutes, trideca-O-acetyl-α-
D-cellotetraosyl trichloroacetimidate 1
57 mg (0.116 mmol) methylene chloride solution (2.0 ml) was added. While cooling the reaction flask to 0 ° C, a solution of trimethylsilyl trifluoromethanesulfonate (45 mg, 0.20 mmol) in methylene chloride (0.50 ml) was added, and the mixture was stirred at 0 ° C for 75 minutes. After adding 40 mg (0.40 mmol) of triethylamine in methylene chloride solution (0.5 ml) at 0 ° C., the solution was diluted with 10 ml of ethyl acetate at room temperature. The suspension was filtered over Celite, and the filtrate was washed once with 10 ml of saturated aqueous sodium hydrogen carbonate solution and then with 10 ml of saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (benzene / acetone = 8 (volume ratio)) to give 1,3-di-O-dodecyl-2-O- (trideca-O-acetyl-β- as white powder. 180 mg (yield 95%) of D-cellotetraosyl) -glycerol was obtained. 180 mg (0.110 mmol) of this compound was added to 4.0 ml of methanol.
Then, 0.40 ml of a 0.5N sodium methoxide methanol solution was added. After stirring at room temperature for 5 minutes, 3
A white precipitate formed upon standing overnight at ° C. This was filtered off, washed with a small amount of methanol, and this white powder was recrystallized twice from methanol, and dried to obtain 89 mg (yield 75%) of the target compound as a white powder. FIG. 4 shows a polarization micrograph of a 30 wt% aqueous solution of this product. Hydrated crystal-lamella liquid crystal phase transition temperature Tm of this product
Was 59 ° C. The infrared absorption spectrum of this product is
3600-3300cm-1,2930cm-1,1660cm-1,1160cm-1,1140-99
It showed absorption at 0 cm-1.

[0009]

Example 3 Hepta-O-acetyl-in Example 1.
By using the corresponding acetyl oligosaccharide α-trichloroacetimidate instead of α-D-cellobiosyltrichloroacetimidate, the following compounds were obtained by the same procedure. 1,3-di-O-dodecyl-2-O- (β-D-glucosyl) -glycerol Tm = 51 ° C 1,3-di-O-dodecyl-2-O- (β-D-cellotriosyl) -glycerol Tm = 63 ° C. 1,3-di-O-dodecyl-2-O- (β-D-cellohexaosyl) -glycerol Tm> 90 ° C. 1,3-di-O-dodecyl-2-O- (β-D- Maltosyl) -glycerol Tm = 47 ° C. 1,3-di-O-dodecyl-2-O- (β-D-maltotetraosyl) -glycerol Tm = 59 ° C. 1,3-di-O-dodecyl-2- O- (β-D-maltohexasil) -glycerol Tm> 90 ° C

[0010]

The compound of the present invention has a hydrated crystal-lamella liquid crystal phase transition temperature of 90% or more, which is obtained by observing a 30% by weight aqueous solution thereof on a hot stage and observing with a polarizing microscope.
It can be confirmed that a sufficiently stable lamellar liquid crystal is formed up to ℃. Further, an aqueous solution having a concentration of 1% by weight or less of these compounds is shaken by hand or subjected to ultrasonic treatment to obtain vesicles having a size of several nanometers to several microns. By pre-dissolving a water-soluble drug in distilled water, the molecular assembly containing the drug in the aqueous solution region of the endoplasmic reticulum is mixed with a hydrophobic substance. A molecular assembly in which the compounds coexist is obtained. Furthermore, a very small amount of it is dissolved in an organic solvent and developed on the air-water interface by the Langumuir-Blodgett method to easily obtain a monomolecular film with hydrophobic groups facing the atmosphere.

[0011]

[Brief description of drawings]

FIG. 1 is a polarization micrograph of Example 1.

FIG. 2 is a differential scanning calorimetry graph of Example 1.

FIG. 3 1H-NMR spectrum of Example 1.

FIG. 4 is a polarization microscope photograph of Example 2.

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[Procedure amendment]

[Submission date] March 18, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Figure 1

[Correction method] Change

[Correction content]

1 is a diagram showing a structure of a lamella liquid crystal phase of the compound obtained in Example 1. FIG.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Fig. 4

[Correction method] Change

[Correction content]

4 is a diagram showing a structure of a lamellar liquid crystal phase of the compound obtained in Example 2. FIG.

Claims (1)

[Claims] 1. A general formula: (R is an oligosaccharide residue having glucose, galactose or mannose as a constituent sugar unit and having a reducing end), an ether type 1,3-glycero oligoglycolipid.