Preparation method, intermediate and application of fucosylated chondroitin sulfate trisaccharide

A chondroitin sulfate and fucosification technology, which is applied in the preparation of sugar derivatives, chemical instruments and methods, esterification saccharides, etc., can solve the problems of low yield, cumbersome fucose side chain connection steps, and no chemical Synthesize fucosylated chondroitin sulfate trisaccharide repeating units, etc., to achieve the effect of high-efficiency technical route and strong anti-inflammatory activity

Active Publication Date: 2019-06-21
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2013, the Tamura research group of Tottori University in Japan synthesized the trisaccharide repeating unit analogue of fucose chondroitin sulfate for the first time (Tetrahedron Lett, 2013, 54, 3940-3943). In the specific synthesis, galactosamine was linked to glucose The yield is low (40%), and the linking step of fucose side chain is also comparatively loaded down with trivial details, needs to improve
Its synthetic raw material disaccharide comes from the acid hydrolysis of chondroitin sulfate, but this disaccharide requires multi-step and complex functional group protection, and there is still room for improvement in the synthesis efficiency
[0008] At present, there is no report on an efficient method for chemically synthesizing fucosylated chondroitin sulfate trisaccharide repeating units in the prior art

Method used

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  • Preparation method, intermediate and application of fucosylated chondroitin sulfate trisaccharide
  • Preparation method, intermediate and application of fucosylated chondroitin sulfate trisaccharide
  • Preparation method, intermediate and application of fucosylated chondroitin sulfate trisaccharide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Synthesis of glucuronic acid donor 7:

[0060] Using commercially produced β-pentaylglucose 15 as a raw material, first add glucosinolate to the 1-position, and then remove the acetyl group in sodium methoxide, and "one-pot method" protect the 4 and 6 positions with benzaldehyde acetal to obtain 14, Then selectively protect the 3-position with a p-methoxybenzyl group under low temperature conditions, and then protect the 2-position with a benzoyl group, and then remove the acetal under the condition of 80% acetic acid, and the 2,2,6,6- Under the conditions of tetramethylpiperidine oxide and iodobenzene diacetate, the 6-position was selectively oxidized to an acid and protected with benzyl to obtain 10, and finally the 4-position was protected with levulinyl to obtain the glucuronic acid donor 7. (Ac=acetyl, Ph=phenyl, Bn=benzyl, Bz=benzoyl, Lev=levulinyl, PMB=p-methoxybenzyl, Tol=p-tolyl)

[0061]

[0062] Synthesis of Compound 14:

[0063] Dissolve β-pentaacetylgl...

Embodiment 2

[0082] Synthesis of the galactosamine receptor:

[0083] Using D-galactosamine as raw material, use 1H-imidazole-1-sulfonyl azide hydrochloride to convert the 2-position to azide, and then obtain the acetylated product 17 under the conditions of pyridine and acetic acid. In trifluoromethanesulfonic acid Under the conditions of p-methoxyphenol and p-methoxyphenol, the terminal group of p-methoxyphenol product 16 was obtained, followed by deacetylation with sodium methoxide, and the 4 and 6 positions were protected with benzaldehyde acetal, and the acceptor 8 was obtained in one pot. (MP is p-methoxyphenyl)

[0084]

[0085] Synthesis of compound 17:

[0086] Dissolve galactosamine hydrochloride (5g, 23.25mmol) in 100mL of methanol, then add potassium carbonate (8g, 58.13mmol), anhydrous copper sulfate (42mg, 0.23mmol), 1H-imidazole-1-sulfonyl azide Nitrogen hydrochloride (6g, 34.88mmol), the reaction solution was stirred at room temperature for 3 hours, TLC monitored the r...

Embodiment 3

[0095] Synthesis of Fucose Donor 9:

[0096] The fucose donor, 9, is accomplished by the following steps. Using L-fucose as raw material, under the conditions of pyridine and acetic anhydride, the peracetylated product was obtained, and then directly reacted with p-cresylthiophenol to obtain the βthiophenol product 20, and then deacetylated in sodium methoxide, and dibutyl Under the condition of tin oxide, the selective benzyl at the 3-position gave 19, and the remaining hydroxyl was protected with allyloxycarbonyl to give the donor 9. (Alloc=allyloxycarbonyl)

[0097]

[0098] Synthesis of compound 20:

[0099] L-fucose (1 g, 6.10 mmol) was dissolved in 10 mL of pyridine and 5 mL of acetic anhydride, and reacted at room temperature for 8 h. TLC showed that the reaction was complete, and the solvent was spin-dried to obtain a yellow liquid (2.02 g, 100%). Then the yellow liquid and p-cresol (1.5g, 12.16mmol) were dissolved in 30mL of dichloromethane, and boron trifluorid...

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Abstract

The invention discloses a synthesizing method of a fucosylated chondroitin sulfate trisaccharide repeat unit. The synthesizing method takes beta-penta-acetyl glucose, D-galactosamine hydrochloride andL-fucose, which are easy to acquire, as raw materials to synthesize monosaccharide glycosylation precursors, and performing glycosylation reaction twice and a series of protecting group conversion toobtain a target product. Under activity test, a prepared fucosylated chondroitin sulfate trisaccharide presents high anti-inflammatory activity and has a good medical application prospect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a preparation method of fucosylated chondroitin sulfate trisaccharide, a key intermediate, and an application of the trisaccharide. Background technique [0002] Fucosylated chondroitin sulfate is a kind of chondroitin sulfate derivative isolated from the body wall of sea cucumber. Its main chain structure is mainly composed of D-glucuronic acid, N-acetylamino D-galactose through β1-3 glycoside The chondroitin sulfate E skeleton is connected by bonds, and the branched chain is composed of fucose that connects the 3-position of D-glucuronic acid to different sulfated sites through α1-3 glycosidic bonds (J.Biol.Chem.1988.263, 18176-18183), and its repeat unit structure is as follows. [0003] [0004] Fucosylated chondroitin sulfate has a unique structure and diverse activities. In addition to anticoagulant and antithrombotic activities, it can also be anti-in...

Claims

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Application Information

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IPC IPC(8): C07H11/00C07H13/08C07H1/00A61P29/00
CPCY02P20/55
Inventor 秦红波何海清陈东赵金华李成季姜玲王韵李晓梅杨雯娇
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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