JPS5928563B2 - Novel azido 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 from 0 to 120.

) 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. On the other hand, heparin, a mucopolysaccharide present in animal tissues, has a strong anti-blood coagulation effect.
It has a wide range of physiological effects such as lipid serum clarifying action, and is characterized by having sulfated amino sugar units, such as the following units, in its molecule.

r (wherein, X represents H or SO3-.

) 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. In the process, they succeeded in synthesizing a new azido sugar polymer containing an azide group, which is a precursor of an amino group, in the molecule, leading to the completion of the present invention.

The present invention will be explained in detail below.

The monomer serving as the raw material of the present invention is 3-azido 1,6-anthro-3-deoxy-2,4-di0-benzyl-β
-0-glucopyranose (7), and is a compound synthesized for the first time by the present inventors.

Below, the synthesis process is illustrated and a specific example thereof is shown.

(However, in the formula, Bz represents a benzoyl group, Bn represents a benzyl group, and Ms represents a methanesulfonyl group.

) First, the starting compound (2) can be easily obtained by treating 1,6-anthro-β-D-glucopyranose (1) derived from β-D-glucopyranose with benzoyl chloride. [M. Cenly
etal. ,CollectiOnCzechOslO
v. ．． Chem. Commun. vOl. 26, 254
2 (1961). ] Compound (2) 21y was dissolved in 500 ml of dry pyridine and cooled on ice.

Methanesulfonyl chloride 197 was added dropwise while stirring, and the temperature was gradually returned to room temperature. After 3 hours, the mixture is poured into a large amount of ice water and stirred to precipitate crude crystals of compound (3).

▲ Separately, after washing with water and drying, recrystallization from methanol gives white crystals 177 (yield 68%). Compound (3) 10y
Dissolve in 50ml of chloroform and cool on ice.

A sodium methoxide solution prepared by dissolving metallic sodium 47 in 60 ml 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. Silica gel column chromatography (developing solvent chloroform-methanol, 100:
1v/v), compounds (4-a) and (4-b)
A mixture of 3.17 (yield 97%) is obtained. [Compound (4)
-Physical properties of mixture of a) and (4-b)] Compound (4
Dissolve 6.77 ml of the mixture of -a) and (4-b) in 300 ml of dry tetrahydrofuran, add 2.87 ml of sodium hydride (purity 60%) under ice cooling, and stir for 30 minutes.

Add benzyl bromide 167 and react at room temperature for 4 hours.
Add ice-cooled saturated aqueous ammonium chloride solution, stir for 30 minutes, and then extract three times with 200 ml of ether.

After drying the extract over anhydrous magnesium sulfate, it was concentrated under reduced pressure.
The resulting oil was purified by silica gel column chromatography (
When purified using a developing solvent (benzene-ethyl acetate 20:1 v/v), an oily mixture of compounds (5-a) and (5-b) 107 (yield: 86%) is obtained. [Compound (5-a
) and (5-b)] Compound (5-a)
) and (5-b) mixture 107 in 200ml of ethanol.
Dissolve 1 in a mixed solvent of 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. When purified by column chromatography on silica gel (developing solvent: benzene-ether, 20:1 v/v), a mixture of compounds (6-a) and (6-b) 9.6f
(yield 81%). [Compounds (6-a) and (6-b
Physical properties of the mixture of compounds (6-a) and (6-b)
) mixture 9.37% in 180ml of dry tetrahydrofuran
1 and chill on ice.

After adding 1.97 g of sodium νum hydride (purity 60%) and stirring for 30 minutes, 11.57 g of penzyl bromide was added. After stirring at room temperature for 3 hours, ice-cooled saturated ammonium chloride aqueous solution 500
Add m1 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/
When purified by v), oily compound U7) 87 (yield 68%)
get. It crystallizes if left standing and can be recrystallized from cyclohexane. [Physical properties of compound (7)] M. p. 2 51.5-52.0℃ Specific optical rotation: [α] 25-15゜(C=1, Chloropho D
Lum) 1. R. (KBr)C7rL-1:2100) 160
0) Elemental analysis: Calculated value as C2OH2lO4N3 C
) 65.38; H) 5.76: N) 11.44 Actual value C) 64.98; H) 5.74; N) 11
．． 38 The thus obtained compound (7) is polymerized by the following method to obtain the azido sugar polymer of the present invention.

Polymerization is carried out by dissolving compound (7) in a suitable solvent and reacting it with a Lewis acid.

Suitable solvents include methylene chloride and the like. Examples of the Lewis acid include phosphorus pentafluoride, antimony pentafluoride, and boron trifluoride etherate, but phosphorus pentafluoride is most suitable from the viewpoint of yield and stereoregularity of the resulting polymer. The amount of Lewis acid used is 2 to 2 with respect to compound (7).
0 mol % is suitable, especially 5 to 7 mol %. During this reaction, if benzoyl fluoride is added in advance, decomposition of the azide group by Lewis acid can be suppressed. In order to prevent the Lewis acid used at this time from remaining in the polymerization tube, the amount of benzoyl fluoride is preferably about 2 times the mole of the Lewis acid. The reaction temperature is approximately -30 to -60°C, and Y
Polymerization time is usually 2 hours or more, generally about 20 to 3 hours.
0 hours is appropriate.

During the main polymerization reaction, it is preferable that the compound 7), the polymerization initiator, and the solvent are thoroughly dried in advance, and the reaction system is also kept in a dry state.

Further, the main polymerization reaction is preferably carried out in vacuum or in an inert gas (eg, N2 gas) atmosphere.

Below, specific examples of the method of the present invention will be explained.

Compound (7) used is one that has been repeatedly recrystallized from sufficiently dried cyclohexane. All reaction operations are 1
The reaction was carried out in a glass ampoule under a high vacuum of 0-57!1 mHg, and the form of the reaction was as shown below.

By cooling the polymerization tube with liquid nitrogen, methylene chloride and benzoyl fluoride are distilled under vacuum, parachlorobenzenediazonium phosphorus hexafluoride salt is thermally decomposed, and phosphorus pentafluoride is introduced into the polymerization tube. The polymerization tube was disconnected from the vacuum line and reacted in an ethanol bath at -60'C for 30 minutes.
Next, a methylene chloride solution of compound (7) is mixed into the polymerization tube. After reacting for a predetermined time, the polymerization tube is opened, methanol is added to stop the polymerization reaction, the solution is dissolved in chloroform, neutralized, washed with water, and then dried.

Repeating the operations of concentration, reprecipitation, and dissolution, the unreacted compound 7
) is completely removed and then freeze-dried from benzene to obtain the azide sugar polymer (8) of the present invention. (However, in the formula, En represents a benzyl group, and n represents an integer from 70 to 120.

) Hereinafter, the present invention will be explained with reference to Examples.

Example 1 1,6-anhtrow 3-azido-2 4
-di-10-benzyl-3-deoxy-β-D~glucopyranose (7) (0.50y) 1.36mm01)
was vacuum-dried overnight under a high vacuum of 10=5 mmHg, and methylene chloride (1
．． 0 ml) in a vacuum ampoule.

This solution was reacted in advance in a polymerization tube at -60°C for 30 minutes.
After mixing in methylene chloride (0.3 ml) and 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 solution is concentrated, and petroleum benzine is added to reprecipitate it. The operations of dissolution, concentration, and reprecipitation are performed two more times, then dissolved in benzene and freeze-dried to obtain 0.40937 of polymer (8-a) (conversion rate 81.9%). Examples 2 to 4 Table 1 shows the results of a reaction conducted in the same manner as in Example 1 while changing the amount of compound (7) used and the polymerization time.

Claims (1)

[Claims] 1. An azido sugar polymer represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein, Bn represents a benzyl group, and n represents an integer from 70 to 120). 2 Structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, Bn represents a benzyl group.) A compound represented by the following is polymerized in the presence of a Lewis acid catalyst, and the formula: ▲Mathematical formula, chemical formula , tables, etc.▼ (However, in the formula, Bn is the same as above, and n represents an integer from 70 to 120.) A method for producing an azido sugar polymer, which is characterized by obtaining a polymer represented by: 3 Claim 2 in which the Lewis acid is phosphorus pentafluoride
Manufacturing method described in section.