Preparation methods of distearoyl phosphatidyl ethanolamine and amino polyethylene glycol derivatives thereof

A technology of distearoylphosphorylethanol and stearoylphosphorylethanolamine, which is applied in the field of preparation of distearoylphosphorylethanolamine and its amino pegylated derivatives, which can solve the difficulty of tracking the reaction process and low temperature requirements It is easy to operate, reduce the cost of raw materials, and achieve the effect of mild conditions

Active Publication Date: 2010-08-18
SOUTHEAST UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above-mentioned protecting groups have a common shortcoming, that is, the reaction process is difficult to track
[0007] In the reported DSPE prepa...

Method used

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  • Preparation methods of distearoyl phosphatidyl ethanolamine and amino polyethylene glycol derivatives thereof
  • Preparation methods of distearoyl phosphatidyl ethanolamine and amino polyethylene glycol derivatives thereof
  • Preparation methods of distearoyl phosphatidyl ethanolamine and amino polyethylene glycol derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0029] The preparation of embodiment 1.2-hydroxyethylcarbamate benzyl ester

[0030] Mix 12mL of ethanolamine in 300mL of dioxane and water mixed solvent (1:1), add 100mg of N,N-dimethylaniline, 32mL of benzyloxycarbonyl chloride and 28mL of triethylamine respectively, and stir the mixture at room temperature for 12h , and the solvent was removed under reduced pressure to obtain a viscous solution. It was diluted with 200 mL of dichloromethane and 100 mL of water, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL×3). The organic layers were combined, washed twice with 0.1M aqueous hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 37.0 g of a white crude product. The obtained crude product was heated and dissolved with 65 mL of petroleum ether / ethyl acetate mixed solvent (40 mL of ethyl acetate, 25 mL of petroleum ether) to obtain a milky white solution, which ...

Embodiment 2

[0031] Embodiment 2. Preparation of compound II

[0032] In a 1000mL dry three-necked flask with a thermometer inserted, add 250mL of dry anhydrous tetrahydrofuran under nitrogen protection, add 3.6g of triethylamine after cooling to 0°C, and then slowly dropwise add 0.34g of POCl 3 50mL of anhydrous tetrahydrofuran solution, kept at 0°C and continued to stir for 0.5h. Dissolve 18.6g of 1,2-distearylglyceride in 250mL of anhydrous tetrahydrofuran, and then slowly add it dropwise to the above reaction solution, controlling the temperature of the reaction solution not higher than 0°C, and the addition is completed in about 2.5h. Stirring was continued for 1 h at 0 °C, then overnight at room temperature. Below 10°C, slowly dropwise add 5.8g of benzyl 2-hydroxyethylcarbamate and 3.6g of triethylamine in anhydrous tetrahydrofuran (100mL), stir at room temperature for 24h, then add 15mL of water to terminate the reaction , the organic solvent was evaporated under reduced pressure,...

Embodiment 3

[0034] The preparation of embodiment 3.DSPE

[0035] Add 1.9g II to 600mL ethanol / dichloromethane (1:1) mixed solvent, heat to 50°C to obtain a colorless and clear solution, then add 0.5g 10% palladium carbon, under 10 atmospheres of hydrogen, at 50°C Reaction 4h. After the reaction was completed, it was filtered while it was hot, and the filtrate was concentrated to 150 mL, a white solid was precipitated, cooled and left for 3 hours, and filtered to obtain a crude product. Recrystallized with ethanol / dichloromethane mixed solvent to obtain 1.3 g of white solid (yield 82%).

[0036] IR (v, cm -1 ): 3263s(-NH), 2917vs(Alkyl), 1737vs(O=C-O), 1627s(-NH), 1265vs(COO-C); ESI-MS(m / z): 746[M-H] - ,748[M+H] + ; 1 H-NMR (300MHz, CDCl 3 ): δ=5.20-5.17 (m, 1H, CH 2 -C H -CH 2 ), 4.12-3.99 (m, 4H, O-C H 2 -C H 2 -O), 3.48-3.27(m, 2H, OP-OC H 2 ), 3.14-3.08 (m, 2H, OP-OC H 2 ), 2.30 (br, 4H, (C H 2 CO) 2 ), 1.58 (br, 4H, (C H 2 CH 2 CO) 2 ), 1.41-1.12 (m, 56H, alkyl...

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Abstract

The invention discloses preparation methods of distearoyl-phosphoethanolamine and amino polyethylene glycol derivatives thereof and relates to effective preparation methods of a medicinal carrier material phospholipids-distearoyl-phosphoethanolamine (DSPE for short) and amino polyethylene glycol derivatives of the distearoyl-phosphoethanolamine (NH2-PEG-DSPE for short). The preparation method of the distearoyl-phosphoethanolamine comprises the following steps of: firstly reacting phosphorus oxychloride with 1,2-distearoyl-glyceride to obtain phosphorylcholine monoester which is I for short; reacting the phosphorylcholine monoester with 2-hydroxyethyl-benzyqcarbamate to obtain DSPE containing amino-protecting group which is II for short; and carrying out catalytic hydrogenation on the II to remove the protecting group to obtain DSPE. The preparation method of the amino polyethylene glycol derivatives of the distearoyl-phosphoethanolamine comprises the following steps of: reacting DSPE with nitrine substituted PEG chloro-carbonic ester which is VI for short to obtain nitrine-polyethylene glycol DSPE derivatives which is III for short; and reducing the nitrine into amino by catalytic hydrogenation to obtain the amino polyethylene glycol derivatives of the distearoyl-phosphoethanolamine.

Description

technical field [0001] The present invention relates to a kind of pharmaceutical carrier material phospholipid --- distearoyl phosphorylethanolamine (represented as DSPE for short) and its aminopegylated derivatives (abbreviated as NH 2 - PEG-DSPE representation) effective preparation method. Background technique [0002] Liposome is a widely used pharmaceutical carrier material, which can form a unique phospholipid bilayer oriented arrangement structure, which can not only encapsulate hydrophilic drugs in the inner water phase, but also encapsulate lipophilic drugs. Based on the phospholipid bilayer, liposomes can effectively delay drug release and improve bioavailability after intravenous injection. In addition, liposomes have good compatibility with biological membranes and low toxicity. Pharmaceutical liposome materials are usually composed of phospholipids and additives, in which phospholipids are the main components that constitute the physical and biological propert...

Claims

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Application Information

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IPC IPC(8): C07F9/10C08G65/48
CPCY02P20/55
Inventor 苟少华房雷
Owner SOUTHEAST UNIV
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