JPH08245682A - 1,3-bisphytanylgliceryl ether-type oligosaccharide glycolipid - Google Patents

Abstract

PURPOSE: To obtain the subject new glycolipid as a specific 1,3- bisphytanylgliceryl ether-type oligosaccharide glycolipid and having excellent chemical stability and hydration swelling ability, and useful for dispersant, humectant, a material for drug carrier and a biocompatible material, etc. CONSTITUTION: The objective new 1,3-bisphytanylgliceryl ether-type oligosaccharide glycolipid is expressed by formula I ((n) is an integer of >=1). The compound is useful as a cosmetic, a food, a dispersant such as a dye, an emulsifier, a stabilizer, a solubilizer, a humectant and a penetrant or as a material for a drug carrier keeping a water-soluble drug in a microcapsule, and further, as a biocompatible material an organic film material, a raw material of an organic substrate relating to semiconductor and a surface modifier of fibers, plastic, metal and ceramic, etc. The compound is obtained by reacting phytanyl alcohol of formula II with epichlorohydrine in the presence of a salt to obtain 1,3-bisphytanylgliceryl ether and reacting with maltoligosaccharide α-trichloroacetoimidate.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a 1,3-bisphytanyl glyceryl ether type oligoglycoglycolipid. This is, for example, cosmetics, food, dispersants such as dyes, emulsifiers, stabilizers, solubilizers, wetting agents, penetrants, or as a drug carrier material for trapping water-soluble drugs in the endoplasmic reticulum, Further, it is suitable as a biocompatible material, or as a raw material of an organic thin film or a semiconductor-related organic substrate, or as a surface modifier such as fibers, plastics, metals, ceramics, and glass.

[0002]

Conventionally, polyethylene-based surfactants and sugar esters have been known as nonionic surfactants used in industrial fields such as foods, cosmetics and dyes.
This polyoxyethylene-based surfactant 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. In addition, sugar esters have a disadvantage that they are acidic and easily hydrolyzed, and are mixtures of isomers and analogs having different positions and numbers of hydroxyl groups to be esterified. In addition, natural oligoglycolipids exist in a state where a plurality of oligosaccharide hydrophilic parts having similar structures exist in a mixed state, and also have a fatty acid part of various lengths in a hydrophobic diglyceride part. It is very difficult to obtain a highly purified product by purification. On the other hand, it is known to produce synthetic glycolipids having a linear alkyl hydrophobic chain (Tetrahedron Lett., Vol. 24, p. 1229 (19
83)). However, the linear long-chain synthetic glycolipid thus obtained has a disadvantage that the solid-liquid crystal phase transition temperature is high, the hydration is difficult to progress, and the swellability is poor, and the dispersibility and the solubilizing ability are low. Have. Synthetic glycolipids having short linear chains have a low phase transition temperature and improved swelling, but have the disadvantage of low barrier and retention ability of closed vesicles.

[0003]

DISCLOSURE OF THE INVENTION The present invention can be produced on a gram scale in a short stage with good purity, and has excellent chemical stability, excellent swellability in hydration in an aqueous solution, and furthermore, lamellae. An object of the present invention is to obtain an oligosaccharide glycolipid having high temperature stability in a liquid crystal phase and capable of forming a vesicle having a high barrier property against a water-soluble substance in a wide temperature range.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors, an amphipathic compound having 1,3-bisphytanyl glyceryl ether as a hydrophobic part and an oligosaccharide as a hydrophilic part is suitable for the purpose. The present invention was found and the present invention was completed. That is, according to the present invention, the following formula (I)

[0005]

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There is provided a 1,3-bisphytanyl glyceryl ether type oligoglycoglycolipid represented by the formula (n represents an integer of 1 or more). 1,3 represented by the formula (I)
-A bisphytanyl glyceryl ether type oligoglycoglycolipid can be prepared by the four steps shown in the following scheme.

[0007]

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First, in the first step, phytol (A) is hydrogenated to form phytanyl alcohol (B).
And Ethyl acetate and ethanol or a mixture thereof can be used as the hydrogenation solvent. Activated carbon-supported palladium can be used as the hydrogenation catalyst. A hydrogen pressure of 1 atm is sufficient. A reaction temperature of room temperature is sufficient. A reaction time of 2 hours is sufficient. After the reaction, palladium on activated carbon is removed by filtration and the solvent is distilled off under reduced pressure to obtain the desired phytanyl alcohol (B) as an oily substance.

In the second step, 1,3-bisphytanyl glyceryl ether (C) can be obtained by reacting phytanyl alcohol (B) with epichlorohydrin in the presence of a base. As a reaction solvent, T
HF is suitable. As a base for this reaction, sodium hydride or potassium hydride can be used. The reaction temperature is suitably 60 ° C. or higher. A reaction time of at least 12 hours is sufficient. At this time, the addition of hexamethylphosphoric triamide gives good results.

In the third step, 1,3-bisphytanyl glyceryl ether (C) is coupled with maltooligosaccharide α-trichloroacetimidate (D) to stereoselect the β-glycosylated form (E). You can get it. As a reaction solvent, a halogenated solvent such as chloroform, methylene chloride, and 1,2-dichloroethane, acetonitrile, and nitromethane can be used, and methylene chloride is suitable. As the Lewis acid catalyst for this reaction, trimethylsilyl trifluoromethanesulfonate and boron trifluoride / ether complex can be used. The reaction temperature is suitably -25 ° C or higher.
A reaction time of 45 minutes or more is sufficient. At this time, stirring in the presence of the molecular sieve 4A gives good results.

In the fourth step, the glycosyl compound is treated with sodium or potassium alcoholate to obtain 1,3-bisphytanyl glyceryl ether type oligosaccharide glycolipid (F) as a white powder. An appropriate reaction temperature is 0 ° C. or higher. The reaction solvent is
An alcoholic solvent such as methanol or ethanol, or a mixed solvent of an ethereal solvent such as diethyl ether or THF and an alcoholic solvent is suitable. As a recrystallization solvent, methanol is suitable. In the case of the above scheme, compound D is D-maltotriose, but by replacing it with an appropriate oligosaccharide, a compound of formula (I) having a maltooligosaccharide of a desired size can be obtained.

In the compound represented by the above formula (I) of the present invention, n is preferably 2 to 6, more preferably 3 to 5.
Is. The compound of the present invention exhibits a characteristic absorption derived from a hydroxyl group at 3500 to 3000 cm ^-1 in an infrared absorption spectrum, and has a δ value of 0.5 to 5 in 1H-NMR.
0.8ppm, 0.9-1.4ppm, 2.9-4.4ppm
At the position of, the signals assigned to the hydrogen of the methyl group of the long-chain alkyl group, the hydrogen of the methylene group of the long-chain alkyl group, the hydrogen of the glycerol part and the adjacent methylene and oligosaccharide part can be observed, respectively, and the product Can be identified.

[0013]

Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

Reference Example 1 (hexadeca-O-acetyl-α
-Method for producing D-maltopentaosyltrichloroacetimidate) D-maltopentaose 1 g (2.0 mmol) and N,
N-dimethylaminopyridine 5 mg and pyridine 15
Dissolve in milliliter and stir at 0 ° C with acetic anhydride
1.5 grams (15 mmol) was added. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (chloroform / methanol =
9/1 (volume ratio) to obtain tetradeca-
1.9 grams (100% yield) of O-acetyl-D-maltopentaose were obtained as a white powder. This compound (1.9 g, 2.0 mmol) was dissolved in DMF (20 ml), and hydrazine acetate (260 mg, 2.8 mmol) was added to the solution.
The mixture was heated and stirred for 2 hours. The solution was cooled to room temperature, diluted with 100 ml of ethyl acetate, and diluted with 100 ml of saturated saline.
Washed twice. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 (volume ratio)) to give 1.8 g (yield 97%) of 1-hydroxy-D-maltopentaose hexadecaacetate as a white powder. Obtained. Dissolve 1.8 grams (1.9 mmol) of this compound in 20 milliliters of methylene chloride and add trichloroacetonitrile
500 mg followed by 120 mg cesium carbonate were added. After stirring at room temperature for 5 hours, it was filtered over Celite,
The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (benzene / acetone = 9/1 (volume ratio)) to obtain 2.0 g (yield 98%) of the target compound as a white powder. This product 1H-N
MR spectrum (in deuterated chloroform, 25 ° C)
A singlet signal was shown at 8.63 ppm, and a doublet signal (spin-spin coupling constant, 3.96 Hz) was shown at 6.47 ppm.

REFERENCE EXAMPLE 2 Maltotriose was used in place of maltopentaose in Reference Example 1, and deca-O was
-Acetyl-α-D-maltotriosyltrichloroacetimidate was obtained as a white powder. 1H-
The NMR spectrum (in deuterated chloroform, 25 ° C.) showed a singlet signal at δ value of 8.72 ppm and a doublet signal at 6.55 ppm (spin-spin coupling constant, 3.62 Hz).

Reference Example 3 (Method for producing 1,3-di-O-phytanylglycerol) 10 ml of an ethyl acetate solution containing 2 g (6.7 mmol) of phytol was added with 0.3% of 5% palladium on activated carbon.
After adding gram and reducing the pressure with a water-jet pump, hydrogen at 1 atm is introduced. After stirring for 1 hour, the suspension was filtered on celite, and the solvent was distilled off under reduced pressure. By purifying the residue by silica gel column chromatography (hexane / ethyl acetate = 9/1 (volume ratio)),
2 g of phytanyl alcohol (yield 10
0%) was obtained. After dissolving 2 g (6.7 mmol) of this compound in 5.0 ml of tetrahydrofuran, 320 mg of sodium hydride and 250 mg of hexamethylphosphoratriamide were added, and the mixture was heated under reflux for 1 hour. To this solution was added 310 mg of epichlorohydrin at room temperature, and the mixture was heated under reflux for an hour. The reaction solution was filtered and concentrated by distilling off the solvent under reduced pressure of a water jet pump.
After adding 10 ml of ethyl acetate, the mixture was washed with 10 ml of a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / hexane).
Purification with ethyl acetate = 20/1 (volume ratio) yielded 1.3 g (60% yield) of the desired compound as an oil.

Example 1 (1,3-di-O-phytanyl-
Method for Producing 2-O- (β-D-maltopentaosyl) glycerol) 100 milligrams of molecular sieve 4A powder in a reaction flask is heated, dried and cooled under reduced pressure to form an argon atmosphere. To this was added a solution of 330 milligrams (0.5 millimoles) of 1,3-di-O-phytanyl-2-propanol in methylene chloride (3.0 milliliters). After stirring for 1 hour, a solution of 822 milligrams (0.5 millimoles) of hexadeca-O-acetyl-α-D-maltopentasyltrichloroacetimidate in methylene chloride (3 milliliters) was added. While cooling the reaction flask to 0 ° C., a solution of 120 mg (0.5 mmol) of trimethylsilyl trifluoromethanesulfonate (0.5 ml) in methylene chloride was added, and the mixture was stirred at 0 ° C. for 90 minutes. After adding a drop of pyridine thereto at 0 ° C., the solution was diluted with 30 ml of ethyl acetate at room temperature. The suspension was filtered on celite, and the filtrate was washed once with 30 ml of a saturated aqueous sodium hydrogen carbonate solution and then with 30 ml of a 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 = 7/1 (volume ratio)) to give 1,3 as white powder.
-Di-O-phytanyl-2-O- (hexadeca-O-acetyl-β-D-maltopentaoosyl) glycerol
910 milligrams (85% yield) were obtained. After dissolving 910 mg (0.43 mmol) of this compound in 5.0 ml of methanol, a 1.0 N sodium methoxide solution in methanol was added.
0.5 ml was added. After stirring at room temperature for 2 hours and standing at 3 ° C. overnight, a white precipitate formed. This was filtered off, washed with a small amount of methanol, and this white powder was recrystallized from methanol three times and dried to obtain 600 mg of the target compound (yield 95%) as a white powder. When this was used as a 0.5% by weight aqueous solution and observed with a differential interference microscope, it was confirmed that it spontaneously hydrated and swelled in water to form myelin-shaped and spherical vesicles.
Its infrared absorption spectrum is 3600-3000 cm ^-1 , 29
50-2800cm ^-1 , 1660-1500cm ^-1 , 1380-1340cm ^-1 , 1160
Absorption was observed at ˜990 cm ⁻¹ .

Example 2 (1,3-di-O-phytanyl-
Method for Producing 2-O- (β-D-maltotriosyl) glycerol) 100 mg of molecular sieve 4A powder in a reaction flask is heated, dried and cooled under reduced pressure to form an argon atmosphere. To this was added a solution of 330 milligrams (0.5 millimoles) of 1,3-di-O-phytanyl-2-propanol in methylene chloride (3.0 milliliters). After stirring for 1 hour, a solution of deca-O-acetyl-α-D-maltotriosyltrichloroacetimidate (530 mg, 0.5 mmol) in methylene chloride (2.5 ml) was added. While cooling the reaction flask to 0 ° C, 120 mg of trimethylsilyl trifluoromethanesulfonate (0.
54 mmol) methylene chloride solution (0.5 ml)
Was added and 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 on celite, and the filtrate was washed once with 30 ml of a saturated aqueous sodium hydrogen carbonate solution and then with 30 ml of a 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 = 7/1 (volume ratio)) to give 1,3-di-O-phytanyl-2-O- (deca-O-acetyl- as white powder. 660 mg (yield 85%) of β-D-maltotriosyl) glycerol was obtained. After dissolving 660 mg (0.42 mmol) of this compound in 5.0 ml of methanol, 0.5 ml of a 1.0 N sodium methoxide methanol solution was added. After stirring at room temperature for 2 hours and standing at 3 ° C. overnight, a white precipitate formed. This was filtered off, washed with a small amount of methanol, and then recrystallized from methanol three times and dried to obtain 450 mg (95% yield) of the target compound as a white powder. The infrared absorption spectrum of this product is 3600-3000 cm ^-1 , 2950-2900 cm ^-1 , 1
650-1580cm- ¹ , 1460-1420cm- ¹ , 1380-1370c
It showed absorption at m ^-1 and 1150-1000 cm ^-1 .

Example 3 (Evaluation of barrier ability of 1,3-bisphytanyl glyceryl ether type oligosaccharide glycolipid vesicle) 1,3-di-O-phytanyl-2-O- (β-D-maltopentao Twenty milligrams of syl) glycerol are weighed into a 30 milliliter round bottom flask, dissolved in chloroform, 5 mole percent of dicetyl phosphate is added, and the solution is added using a water pump. The solvent was distilled off under reduced pressure, and the pressure was further reduced by a vacuum pump overnight to form a lipid thin film on the bottom of the flask. To this lipid thin film, 3 ml of a 0.1 mmol solution of calcein, a water-soluble fluorescent dye, was added and allowed to swell at 30 ° C.
The mixture was shaken by hand to obtain a vesicle dispersion solution of lipids. In a cell chamber of the fluorescence spectrometer, 300 microliters of the above-described lipid vesicle dispersion was added to 2.7 ml of a buffer solution containing no fluorescent dye and maintained at a desired temperature, and the mixture was thoroughly stirred. To this solution, 30 microliters of a 10 mmol aqueous solution of cobalt (II) chloride as a fluorescence quencher was added from outside and mixed well. Using this time as a starting point, the time change of fluorescence intensity is measured using excitation light of wavelength 480.0 nm and wavelength of 515.0 nm, and the permeation rate of calcein from the inner aqueous phase to the outer aqueous phase is measured. Was measured. After the measurement, add enough surfactant Triton to this solution.
An aqueous solution of X-100 (10% by weight, 30 microliters) was added to completely dissolve the lipid in micelles, and it was confirmed that the fluorescence was completely quenched. For comparison, vesicles were prepared from phospholipid dipalmitoylphosphatidylcholine by the same preparation method, and calcein lipid membrane permeation rate was measured by the same measurement method. In FIG. 1, from 30 ° C
The results of plotting the time constant of permeation against the temperature up to 60 ° C are shown. In the entire temperature range of the measurement, the 1,3-bisphytanyl glyceryl ether type oligosaccharide glycolipid vesicle is
Compared to dipalmitoylphosphatidylcholine vesicle, it showed higher barrier ability.

[0020]

Industrial Applicability The compound of the present invention easily hydrates and swells in water at room temperature, and spontaneously forms a spherical aggregate or myelin form. This aggregate is stable in a wide temperature range from room temperature to 90 ° C. A dispersion of closed vesicles (vesicles) having a size of several nanometers to several micrometers can be obtained by hand shaking or sonicating an aqueous solution having a concentration of 1% by weight or less. By dissolving the water-soluble drug in the aqueous solution in advance, a molecular assembly containing the drug in the aqueous solution region in the closed vesicle can be obtained. The closed vesicle comprising the compound of the present invention has an excellent barrier ability as compared with a phospholipid widely used for producing the closed vesicle. Furthermore, by dissolving a trace amount in an organic solvent and developing it on the air-water interface by the Langmuir method, a monomolecular film having a hydrophobic group facing the atmosphere can be easily obtained. The solid substrate can be modified by transferring the monomolecular film on the air-water interface onto the solid substrate by the Langmuir-Blodgett method.

[Brief description of drawings]

FIG. 1 is a view showing the results of evaluating the barrier ability of vesicles prepared from the compounds of the present invention.

Claims (1)

[Claims] 1. The following formula (I): (N in the formula represents an integer of 1 or more) 1,3
-Bisphytanyl glyceryl ether type oligosaccharide glycolipid.