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Sialyl methyl ester methyl glucoside derivative and synthesis method and application thereof

A technology of methyl sialoside and derivatives, which is applied in the preparation of sugar derivatives, sugar derivatives, and sugar derivatives, and can solve the problems of unsatisfactory biological research, low content, and poor membrane permeability.

Active Publication Date: 2018-11-09
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Nevertheless, there are still the following problems to be solved urgently about phenylethanol glycosides: First, although phenylethanol glycosides are widely distributed in the plant kingdom, due to their low content (0.02% to 0.40%), they are difficult to separate The amount of extracted samples is very small, which cannot meet the needs of biological research; secondly, due to the complex structure of phenylethanol glycosides, its synthesis research is also very difficult
In addition, the good hydrophilicity of phenylethanol glycosides leads to poor membrane permeability, which affects its druggability

Method used

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  • Sialyl methyl ester methyl glucoside derivative and synthesis method and application thereof
  • Sialyl methyl ester methyl glucoside derivative and synthesis method and application thereof
  • Sialyl methyl ester methyl glucoside derivative and synthesis method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0088] Example 1 Synthesis of glycosyl ligands (9a, 9b) and cinnamic acid derivatives (10a, 11a, 11b, 12a)

[0089] Reagents and conditions: (a) 9a: allyl bromide, K 2 CO 3 , acetone, reflux overnight, 89%; 9b: isopropylamine, NaOH, Ac 2 O,H 2 O, 81%; (b)i) allyl bromide, K 2 CO 3 , acetone, reflux overnight; ii) MeOH, saturated NaHCO 3 Solution, reflux for 2h, 88% for 10a, 80% for 11a; 11b: DMAP, pyridine, Ac 2 O, 86%; (c) malonic acid, piperidine, pyridine, reflux overnight, 70%.

[0090] Synthesis of 3,4-diallyloxyphenethyl alcohol (9a)

[0091] Add 3,4-dihydroxyphenethyl alcohol (9,0.83g, 5.4mmol, 1.0equiv), allyl bromide (2.59g, 21.6mmol, 4.0equiv) to a 100mL round bottom flask, K 2 CO 3 (3.73g, 27mmol, 5.0equiv), acetone (50mL), heated to reflux for 12h, TLC monitored the reaction to be complete, filtered, concentrated, and column chromatography (ethyl acetate / petroleum ether: 3 / 1) gave the product 1.12g, as Colorless oil, yield 89%.

[0092] 1 H NMR (400MHz,...

Embodiment 2

[0102] Example 2 (3,4-diallyloxyphenyl) ethyl 2,3-di-O-acetyl-6-O-allyloxycarbonyl-β-D-glucopyranoside (compound 16) Synthesis

[0103] Reagents and conditions: (a) TMSOTf, 9a, CH 2 Cl 2 , MS, -72℃, 93%; (b) PPTS, MeCN, H 2 O, reflux, 99%; (c) AllocBt, Et 3 N,CH 2 Cl 2 ,92%.

[0104] (3,4-diallyloxyphenyl)ethyl 2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranoside (compound 14) synthesis

[0105] Add to 250mL two-neck bottle MS (750mg), after baking and cooling, add compound 13 (0.50g, 10.1mmol, 1.0equiv) {references J.Org.Chem., 65 (2000) 2410-2431; J.Am.Chem.Soc., 121 (1999) 734-753; Tetrahedron Lett., 29 (1988) 2299-2302. Prepared} and compound 9a (0.25g, 10.6mmol, 1.05equiv), oil pump vacuum, after Ar protection, add 60mL dry DCM, TMSOTf (20uL) was added at -40°C. After 2 hours, TLC monitored the reaction to be complete. Triethylamine was extracted at low temperature, filtered with diatomaceous earth, concentrated under reduced pressure, and column chromatogra...

Embodiment 3

[0111] The synthesis of embodiment 3 compound 1-5

[0112] Reagents and conditions: (a) DCC, DMAP, CH 2 Cl 2 , 0℃ to r.t.; (b) AcCl, MeOH, CH 2 Cl 2 ; (c) 10% Pd / C, MeOH, H 2 O,HClO 4 or TsOH.

[0113] General synthetic method of compound 18a-e

[0114] Compound 16 (1.0 equiv) and the corresponding acid (1.5 equiv) were dissolved in dichloromethane, DCC (1.5 equiv) and DMAP (1.5 equiv) were added at 0°C, and then stirred at room temperature for 12 hours. The solvent was evaporated to dryness, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 1:4 to 1:3) to obtain the corresponding product.

[0115] (3,4-diallyloxyphenyl)ethyl 2,3-di-O-acetyl-4-O-(3,4-diallyloxyphenyl)acryl-6-O -Synthesis of allyloxycarbonyl-β-D-glucopyranoside (compound 18a)

[0116] Following the general procedure, compounds 16 and 9a were coupled to give compound 18a as a colorless oil in 85% yield. [α] D 25 -9.8 (c 0.008, CDCl 3 ); 1 H NMR (400MHz, CDCl ...

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Abstract

The invention discloses a sialyl methyl ester methyl glucoside derivative, a synthesis method and application thereof. According to the invention, drug design principles such as bioisostere are used to transform acteoside to obtain a series of phenylethanoid glycoside derivative, sialyl methyl ester methyl glucoside derivative and 9-decarboxylate rosmarinicacid compound with neuroprotective activity. The invention further provides a synthesis method of the sialyl methyl ester methyl glucoside derivative. According to neuropharmacological experimental studies, the sialyl methyl eater methyl glucoside derivative provided by the invention can increase cell survival rate, reduce cell apoptosis rate and inhibit the production of intracellular reactive oxygen species through several ways such asanti-apoptosis and anti-oxidative damage, significantly reduce cell damage and play a neuroprotective role. The sialyl methyl ester methyl glucoside derivative provided by the invention has importantapplication potential in preventing or treating neurological diseases including neurodegenerative diseases and cerebral ischemia.

Description

[0001] This application is a divisional application of an invention patent application with the title of "Phenylethanol Glycoside Analogs and Its Synthetic Method and Application", the application number of "201510101527.8", and the filing date of "March 6, 2015". technical field [0002] The present invention relates to sialyl methyl glycoside derivatives. The present invention further relates to the synthesis method of the above derivatives and their application in the prevention or treatment of nervous system diseases, belonging to sialic acid methyl glycoside derivatives and their synthesis methods and applications field. Background technique [0003] The damage or death of nerve cells caused by oxidative stress and free radical damage is a common pathological process of many nervous system diseases (such as neurodegenerative diseases, ischemic stroke, etc.) (Neurologia, 17 (2002) 399-401.) . Neurodegenerative diseases are characterized by gradual loss of structure and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H1/00A61P25/00A61P9/10
Inventor 叶新山刘颖果熊德彩蒲小平李夏溪
Owner PEKING UNIV