JPH07631B2 - Ether-type 1,3-glycero-oligoglycolipid - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel ether type 1,
It relates to a 3-glycero oligoglycolipid. These are used as emulsifiers, stabilizers, dispersants, solubilizers, admixtures, wetting agents, penetrants, viscosity modifiers for foods, cosmetics, dyes, etc., or as fibers, plastics, metals, 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 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 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 of In addition, natural oligoglycolipids exist in a state where multiple hydrophilic oligosaccharides with similar structures are mixed, 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 portion thus obtained undergoes a phase transition from a lamellar liquid crystal phase to a hexagonal bi-liquid crystal phase at high temperature, and thus has a drawback that the lamellar liquid crystal phase has low temperature stability. 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]

The present invention has amphipathic characteristics equivalent to those of natural products, and can be produced in a short step from various oligosaccharides of disaccharide or higher as a high-purity single compound. 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 compound represented by the general formula (I)

[Chemical 2] (R in the formula represents a residue of an oligosaccharide having glucose, galactose or mannose as a constituent sugar unit and having a reducing end and forming a bond at the reducing end position). The present invention provides an ether type 1,3-glycero-based oligoglycolipid. This general formula (I)
All of the compounds represented by are novel compounds which have not been published in the literature, and are produced, for example, from oligosaccharides having glucose, galactose or mannose as a constituent sugar unit and having a reducing end by the following five-step method. be able to. First, the oligosaccharide is acetylated with acetic anhydride in the presence of a base. As a solvent for the acetylation reaction, THF,
An ether solvent such as diethyl ether and pyridine can be used, but pyridine is suitable. As a base for this reaction, an organic base such as pyridine or triethylamine is suitable. It is also possible to use N, N-dimethylaminopyridine 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, etc. can be used,
DMF gives good results. The reaction temperature is suitably 50 ° C. A reaction time of 2 hours is sufficient. Then, this is reacted with trichloroacetonitrile using a base as a catalyst to obtain trichloroacetimidate of acetyl oligosaccharide in which the reducing terminal position is selectively activated in high yield. As a reaction solvent, methylene chloride,
A halogen-based solvent such as 1,2-dichloroethane or chloroform is suitable. As the base, sodium hydride,
DBU and cesium carbonate can be used. 2 at room temperature
When the reaction is carried out under the condition of stirring for more than an hour, α-form trichloroacetimidate is selectively obtained. The 1 H-NMR spectrum (in deuterated chloroform, 25 ° C.) of these compounds shows a δ value of 6.4 to 6.6 pp.
Since a doublet signal (spin-spin coupling constant 3.4 to 4.0 Hz) is shown in m, it can be confirmed that these compounds are α-form imidates. next,
This α-form of trichloroacetimidate can be converted into a compound of the general formula

[Chemical 3] By reacting with 1,3-di-O-dodecyl-3-propanol represented by the formula (3), the β-form glycosyl form can be selectively obtained. As a reaction solvent, a halogen solvent such as chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile, nitromethane can be used, and methylene chloride is suitable. As the Lewis acid catalyst for this reaction, trimethylsilyl trifluoromethanesulfonate or boron trifluoride / ether complex can be used. As the amount of the Lewis acid catalyst used, 1.5 equivalent or more with respect to trichloroacetimidate is used, which gives good results. The reaction temperature is suitably -25 ° C or higher. 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 compound is treated with sodium or potassium alcoholate, and the powder obtained by cooling / filtering or distilling off the solvent is recrystallized to give the ether type 1, represented by the general formula (I).
Yield of 3-glycero-based oligoglycolipid as white powder 70
Obtained at ~ 95%. A suitable reaction temperature is 0 ° C. or higher. As the reaction solvent, an alcohol solvent such as methanol or ethanol, or a mixed solvent of an ether solvent such as diethyl ether or THF and an alcohol solvent is suitable. Examples of the recrystallization solvent include alcohol solvents such as methanol and ethanol, acetone, pyridine, TH
F, or a mixed solvent thereof can be used. The compound of the present invention has an infrared absorption spectrum of 3500 to
Shows characteristic absorption derived from hydroxyl group at 3300 cm ^-1
In H-NMR, the δ value is 0.5 to 0.8 ppm,
Hydrogen at a methyl group of a long-chain alkyl group, hydrogen at a methylene group of a long-chain alkyl group, hydrogen at a glycerol moiety and its adjacent methylene and oligosaccharide moieties at 0.9 to 1.4 ppm and 2.9 to 4.4 ppm. Can be observed, and the product can be identified by them.

[0005]

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

[Reference Example 1] Production method of 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. This was stirred overnight at room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 40 (volume ratio)) to give 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 thereto, and the mixture was heated with stirring at 50 ° C. for 2 hours. After the solution was cooled to room temperature, ethyl acetate 30
It was diluted with ml and washed 7 times with 30 ml of saturated saline. The organic layer was dried over anhydrous sodium sulfate and then 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 1-hydroxy-D-cellotetraose tridecaacetate 345 mg (yield 96%) as a white powder. 310 mg (0.256 mmol) of this compound was dissolved in 7.0 ml of methylene chloride, and trichloroacetonitrile 0.7
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
Trichloroacetimidate 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 cooling the reaction flask 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 a 1.0 N sodium methoxide solution in methanol was added. Stir at room temperature for 2 hours and then at 3 ° C for 1
A white precipitate formed upon standing overnight. This was filtered off, 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 polarization 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 by heating under reduced pressure and cooled to 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 a 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 microscope photograph 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-lamellar liquid crystal phase transition temperature of 90% or more 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 an endoplasmic reticulum 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. In addition, a very small amount of it is dissolved in an organic solvent, and it is developed on the air-water interface by the Langumuir-Blodgett method, so that a monomolecular film with hydrophobic groups facing the atmosphere can be easily obtained.

[0011]

[Brief description of drawings]

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

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

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

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 in the formula represents a residue of an oligosaccharide having glucose, galactose or mannose as a constituent sugar unit and having a reducing end, which forms a bond at the reducing end position). Ether type 1,3-glycero oligoglycolipid.