JPS5928562B2 - Novel amino sugar polymer and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula:
Indicates an integer of 20.

The present invention relates to a novel amino sugar polymer represented by the following formula and a method for producing the same.

Polymers of α-1, 6-linked glucose can be used with microorganisms such as Leuconostoc mesenteroides (
Leuconostocmesenteroides)
There is a dextran produced by.

Dextran itself is useful as a plasma expander, but its sulfate ester (dextran sulfate) has a lipid serum clarifying effect and lowers blood cholesterol and triglycerides. It also has anti-hyaluronidase and fibrinolytic effects, and is known as an effective drug for treating hyperlipidemia and arteriosclerosis. ↓VNノV5↓l! Wisdom
On the other hand, heparin, a mucopolysaccharide present in animal tissues, has a wide range of physiological effects such as strong blood coagulation inhibitory effects and lipid serum clarifying effects, and its molecules contain It is characteristic that it has a sulfated amino sugar, for example, the following units.

(However, in the formula, X is H or SO3 shows.

) Therefore, if it is possible to synthesize polysaccharides and sulfated products thereof that have α-1,6-linked sugar chains such as dextran and also contain amino groups such as heparin in their molecules, various physiological functions can be expected.

However, polysaccharides having free amino groups are not naturally produced, and to date there have been no reports on the artificial synthesis of polysaccharides by polymerization of amino sugar monosaccharides.

Therefore, in view of the above-mentioned purpose, the present inventors have conducted intensive research and have synthesized a polysaccharide having an α-1,6-linked sugar chain and containing an amino group such as heparin in its molecule. They were very successful and completed the present invention.

The present invention will be explained in detail below.

The starting material of the present invention has the formula: (However, in the formula, Bn.n is the same as above.

) is a polymer represented by
It was the first compound to be synthesized. Below, the synthesis process is shown in diagrams, and specific examples thereof are shown.

(However, in the formula, Bz represents a benzoyl group, Ms represents a methanesulfonyl group, and Bn and n are the same as above.

) Compound (2) can be easily obtained by treating 1,6-anthro-β-D-glucopyranose (1) derived from β-D-glucopyranose with benzoyl chloride [M. This door EtalCO
llectiOnCzechOslOv) Chem. C
Ommun. Vol. 26, 2542 (1961).

] Compound (2) 21V was dissolved in 500 ml of dry pyridine and cooled on ice.

Methanesulfonyl chloride 19y was added dropwise while stirring, and the temperature was gradually returned to room temperature. After 3 hours, the reaction mixture was poured into a large amount of ice water and stirred to precipitate crude crystals of compound (3).

After washing with water, drying, and recrystallizing from methanol, white crystals 17V (yield 68%) are obtained [Physical properties of compound (3)] M. P. : 164-5°C Specific rotation: [α] sweet-24 form) IR (KBr) Cm-1 : 1180, 1360, 17
00-1725 elemental analysis: Calculated value as C2lH2OO9S C) 56.25; H) 4.50: S) 7.
15% actual value C, 56.23; H, 4.49; S, 7
．． 18% Compound (3) 10y was dissolved in 50ml of chloroform and cooled on ice.

A sodium methoxide solution prepared by dissolving 4V of metallic sodium in 60ml of methanol is added dropwise to this while stirring.

After the mixture was left at room temperature overnight, it was neutralized with 5% hydrochloric acid and concentrated to dryness under reduced pressure. The residue was extracted five times with 20 ml of acetone, and the extract was concentrated under reduced pressure to obtain an oil. When purified by silica gel column chromatography (developing solvent: chloroform-methanol, 100:1 v/v), compound (4-a) was obtained.
A mixture of (4-b) and 3. IV (97% yield) is obtained.
[Physical properties of mixture of compounds (4=a) and (4-b)] IR (film) -1: 3400 A mixture of compounds (4-a) and (4-b) 6.7y was dried. Dissolve sodium hydride (purity 60%) in 300 ml of tetrahydrofuran and cool on ice.

Add 8y and stir for 30 minutes.

Next, benzyl bromide 167 is added and reacted at room temperature for 4 hours. Add ice-cooled saturated ammonium chloride aqueous solution,
After stirring for 0 min, extract 3 times with 200 ml of ether. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography (developing solvent: benzene monoethyl acetate 20:1 v/v) to obtain an oily compound (5-a). A mixture of (5-b) and 107 (yield: 86%) is obtained. [Physical properties of mixture of compounds (5-a) and (5-b)] Mixture 107 of compounds (5-a) and (5-b) was mixed with 200 TfL of ethanol.
1 and 50 ml of saturated ammonium chloride water, add 17.57 ml of sodium azide, and add 6 while stirring.
Heat to reflux for 0 hours.

After cooling, 500 ml of distilled water is added, ethanol is removed under reduced pressure, and the remaining aqueous solution is extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oil. Purification by column chromatography on silica gel (developing solvent, benzene-ether, 20:1/v) revealed a mixture of compounds (6-a) and (6-b) at 9.61% (
Yield: 81%). [Compounds (6-a) and (6-b)
Physical properties of mixture of compounds (6-a) and (6-b)
9.3y of a mixture of 180ml of dry tetrahydrofuran
Melt and cool on ice.

Add 1.91 sodium hydride (purity 60%) to 30
After stirring for several minutes, 11.5 tons of benzyl bromide is added. 3 at room temperature
After stirring for an hour, ice-cooled saturated ammonium chloride aqueous solution 50
Add 0ml and stir for an additional 30 minutes. This mixed solution is extracted with ether, and the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oil. Silica gel chromatography (developing solvent, hexane-ethyl acetate 5:1v
/v) to produce oily compound (7) 87 (yield 68
%). It crystallizes if left standing and can be recrystallized from cyclohexane.

The compound (7) thus obtained was polymerized by the following method to obtain the azido sugar polymer (8) which is the starting material of the present invention.
).

1,6-Anthitro 3-azido-2,4-di0-benzyl-3-deoxy-β-D-glucopyranose (7)
(0,50f7, 1,36mm01) to 10-5m7!
Vacuum dried under high vacuum of LHg overnight and dissolved in methylene chloride (1.0 ml) previously dried over calcium hydride in a vacuum ampoule.

This solution was reacted in advance in a polymerization tube at -60°C for 30 minutes, and phosphorus pentafluoride (0.068 mm01), benzoyl fluoride (15 μl, 0.14 mm01), and methylene chloride (0.3 mm0) were mixed. After reacting at -60°C for 23 hours, the polymerization ampoule was opened and methanol was poured into it.
At this time, the polymer precipitates, so chloroform is added to it until the polymer is sufficiently dissolved, neutralized with an aqueous sodium bicarbonate solution, washed with water, and dried over anhydrous sodium sulfate. After removing the desiccant, the sap liquid is concentrated and
Add petroleum benzene and re-sediment. The operations of dissolving, concentrating, and reprecipitation were performed two more times, and the polymer (8-a) was dissolved in benzene and freeze-dried to obtain a polymer (8-a) of 0.40937 (conversion rate 8).
1.9%). Table 1 shows the results of carrying out the reaction in the same manner as above while changing the amount of Compound No. 1 used and the amount of compound (7) used and the polymerization time.

In this way, the starting material (8) is obtained, which is reduced by the following method to obtain the amino sugar polymer (9) of the present invention.
get. Polymer (8) may be dissolved in a sufficiently dry suitable solvent, such as tetrahydrofuran, in particular, and reacted with lithium aluminum hydride.

Lithium aluminum hydride has 0.
The amount is required to be 5 times or more by mole, and is suitably about 2.5 to 30 times by mole. The reaction temperature is approximately 60 to 70°C, and the reaction time is approximately 30 minutes to 1 hour, and prolonged reaction is not preferred because side reactions are likely to occur.

Specific examples of the present invention will be explained below.

(However, in the formula, Bn.n is the same as above.) Below,
The present invention will be explained by examples. Example 1 Polymer (8-d) (200, N3 group: 0.544m
The form of the tetrahydrof reaction in which m01) is dried in advance is
There are no particular restrictions.

Usually, the polymer (8) is dissolved in tetrahydrofuran in advance, and lithium aluminum hydride is mixed with the polymer (8) and immediately 66
Increase temperature to ℃. During the reaction, it is best to stir the system to make it homogeneous.

The reaction time is about 1 hour, and a long reaction time is not preferred because side reactions are likely to occur. The reaction is stopped by adding a saturated aqueous solution of potassium sodium tartrate. The polymer is extracted with benzene, washed with water, dried, concentrated, and then lyophilized to obtain the amino sugar polymer (9) of the present invention. Lan (THF) (dissolved in 30 mO).

Claims (1)

[Claims] 1 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Bn is a benzyl group, and n is 70 to 1.
Indicates an integer of 20. ) is an amino sugar polymer represented by 2 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Bn is a benzyl group, and n is an integer from 70 to 120.) The azido sugar polymer represented by the formula is mixed with lithium aluminum hydride. A method for producing an amino sugar polymer characterized by processing to obtain an amino sugar polymer represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Bn and n are the same as above.) .