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Sugar-polyethylene glycol-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) conjugated compound and preparation method and application thereof

A technology for coupling compounds and polyethylene glycol, applied in the field of medicine, can solve the problems of synthetic process reports, complex synthetic processes, difficult post-processing, etc., and achieves the effects of high yield, simple operation, and easy control of reaction conditions.

Active Publication Date: 2019-02-19
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Different types of sugar-PEG-DSPE coupling compounds have high economic value and are mainly used to prepare targeted liposomes. However, the synthesis process of these compounds is complicated and the post-processing is difficult. At present, there are no mature synthetic process reports at home and abroad.

Method used

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  • Sugar-polyethylene glycol-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) conjugated compound and preparation method and application thereof
  • Sugar-polyethylene glycol-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) conjugated compound and preparation method and application thereof
  • Sugar-polyethylene glycol-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) conjugated compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] The synthesis of embodiment 1 compound 2a or 2b or 2c or 2d or 2e

[0092]

[0093] Operation process: Add 1g of glucose (galactose, mannose, maltobiose, maltotriose), 5ml of acetic anhydride, 7ml of pyridine, and 10mg of iodine tablets into a three-necked flask in sequence, and carry out acetylation reaction at 0°C, and 25°C React overnight (there is heat dissipation in the reaction system when just added). The next day, add 8.4g NaHCO 3 Aqueous solution (10ml H 2 O) in 30ml EA, stir for 2h, bubbles are generated, use NaHCO 3 Wash once with aqueous solution, then wash twice with 2M HCl, and spin dry to obtain compound 2a. Results: 4.1 g of a colorless and transparent oily product was obtained, with a yield of 94.7%. 2b, 2c, 2d, 2e were synthesized under the same conditions as 2a.

[0094] NMR analysis of compound 2a:

[0095] H NMR (500MHz; Chloroform-d): δ6.29(d, J=3.2Hz, 1H), 5.67(d, J=7.7Hz, 0.4H), 5.44-5.35(dd, J=10.2and 10.0Hz, 1H),5.29-5.21(m,0.4H),5.17...

Embodiment 2

[0096]The synthesis of embodiment 2 compound 3a or 3b or 3c or 3d or 3e

[0097]

[0098] Operation process: Add compound 2a (2g, 5.1mmol), 3-butyn-1-ol (718mg, 10.2mmol), dichloromethane (20ml) into a 100ml three-necked flask in turn, protect with nitrogen, cool down to 4°C in an ice bath, A solution of boron trifluoride in ether (1.25ml, 10.2mmol) was added dropwise, and reacted overnight at room temperature. On the second day, saturated aqueous sodium bicarbonate solution (30ml) was added to quench the reaction, dichloromethane (50ml) was added to extract, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 2.01g of a yellow semi-oil and semi-solid product, namely compound 2c, collected The rate is 98.0%. 3b, 3c, 3d, 3e were synthesized under the same conditions as 3a.

Embodiment 3

[0099] The synthesis of embodiment 3 compound 4a or 4b or 4c or 4d or 4e

[0100]

[0101] Operation process: Compound 3a (2.01g, 5mmol) and methanol (20ml) were sequentially added into a 100ml three-neck flask, protected by nitrogen, then sodium methoxide (1.35g, 25mmol) was added, and stirred overnight at room temperature. On the second day, add glacial acetic acid (1.8ml, 30mmol) and stir for 10 minutes, spin dry, add deionized water (5ml) to dissolve, purify with ion exchange resin, and spin dry to obtain 1.1g of off-white semi-oil and semi-solid product, that is, compound 4a , yield 94.3%. 4b, 4c, 4d, 4e were synthesized under the same conditions as 4a.

[0102] Compound 4a NMR analysis: 1H NMR (500MHz, Methanol-d4) δ 4.30 (d, J = 7.8Hz, 1H), 3.99-3.92 (m, 1H), 3.86 (dd, J = 11.9, 1.7Hz, 1H) ,3.72–3.63(m,2H),3.35–3.24(m,3H),3.17(dd,J=9.1,7.8Hz,1H),2.54-2.48(m,2H),2.27(t,J=2.7Hz ,1H).

[0103] Compound 4b NMR analysis: 1H NMR (500MHz, Methanol-d4) δ4.25(d, J=7.5Hz, ...

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Abstract

The invention discloses sugar-polyethylene glycol-DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) conjugated compound and a preparation method and application thereof, wherein the sugar-polyethylene glycol-DSPE conjugated compound is prepared by conjugating sugar to DSPE-PEG (polyethylene glycol). The sugar is one of a monosaccharide, a disaccharide, a polysaccharide and the sugar acetylated, wherein the monosaccharide includes mannose, galactose, arabinose and glucose; the disaccharide includes maltose; the polysaccharide is maltotriose. DPSE is artificial phospholipid, having lipotropism; PEG is a hydrophilic substance; a sugar ligand is a target of a targeting material. The compound herein is applicable to the design of targeting carriers, especially liposomes and micelles, and is also applicable as a surfactant. In addition, the invention also provides the preparation method of the compound herein; materials for the preparation method are easy to attain, reaction conditionsare mild and easy to control, the preparation method is simple to perform, the product is easy to purify, and the yield is high. The product is applicable to biological researches and is important tothe preparation of drug carriers and the disease treatment.

Description

technical field [0001] The invention relates to a targeted drug material for modifying nanocarriers, in particular to a sugar-polyethylene glycol-DSPE coupling compound obtained by coupling sugar with polyethylene glycol-DSPE, and a preparation method and application thereof. The invention belongs to the technical field of medicine (drug material). Background technique [0002] Liposomes were first discovered by British scholar Bangham when he dispersed phospholipids in water for electron microscope observation. Phospholipids are dispersed in water to form multilayered vesicles, and each layer is a lipid bilayer. Later, this bimolecular vesicle with a structure similar to a biological membrane is called a liposome. In 1971, British Liman and others began to use liposomes as drug carriers. Since then, liposome, as a new dosage form of targeted drug delivery system, has attracted worldwide attention. Liposome drug delivery system is considered to be one of the most promisin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K9/12A61K47/26A61K47/24C08G65/333C08G65/331
CPCA61K9/1075A61K9/1271A61K47/24A61K47/26C08G65/3318C08G65/33396
Inventor 彭海生杜智敏廉明明李文华唐淑坤李明慧刘肖莹张长梅
Owner HARBIN MEDICAL UNIVERSITY
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