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Preparation method of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine

A technology of phosphorylethanolamine and glycerol, applied in 1 field, can solve the problems of liposome stability, poor membrane fusion transfection efficiency, etc., and achieve the effects of few steps, short routes, and easily controllable conditions.

Pending Publication Date: 2022-08-05
SUZHOU HIGHFINE BIOTECH
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Problems solved by technology

Cationic liposomes can effectively enter cells for transfection, and can avoid immunotoxicity. It is a safe and effective gene therapy carrier. Dyeing efficiency is usually poor

Method used

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  • Preparation method of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine
  • Preparation method of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine
  • Preparation method of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine

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preparation example Construction

[0027] The preparation method of DOPE according to the embodiment of the present invention comprises the following steps:

[0028] Step S1, making (S)-glycerol acetal and diphenyl chlorophosphate undergo a nucleophilic substitution reaction under the action of the first base to obtain [(R)-2,2-dimethyl-1,3-dioxolane Cyclo-4-yl]methyl diphenyl phosphate.

[0029] Specifically, the reaction formula is shown in the following formula (1):

[0030]

[0031] Further, in the step S1, the first base is one or more selected from pyridine, triethylamine, DIEA, sodium carbonate, and sodium hydroxide. Among them, pyridine is preferred, and the reaction yield will be higher.

[0032] Further, in the step S1, the molar ratio of the (S)-glycerol acetal, diphenyl chlorophosphate and the first base is 1:(1-1.5):(1-1.8); the reaction temperature is 0~35℃, the reaction time is 1~10 hours. Preferably, the molar ratio of (S)-glycerol acetal, diphenyl chlorophosphate and base is 1:1.0:1.3. ...

Embodiment 1

[0060] (1) Preparation of [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl diphenyl phosphate (I)

[0061] Dissolve 20g (S)-glycerol acetal in 300mL of dichloromethane in a three-necked flask, add 15.6g of pyridine, drop it into an ice-water bath, dropwise add 100mL of diphenyl chlorophosphate in dichloromethane solution, and keep the internal temperature for the reaction 2h. TLC monitored the complete reaction of the raw materials, the reaction solution was washed with 150 mL of 1M HCl, and then washed twice with 150 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain [(R)-2,2-dimethyl-1,3- Dioxolane-4-yl]methyl diphenyl phosphate (I) 50.7 g, yield 92%.

[0062] (2) Preparation of (R)-2,3-dihydroxypropyl diphenyl phosphate (II)

[0063] In a three-necked flask, 20 g of [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl diphenyl phosphate (I) was dissolved in 160 mL of a mixed solvent of methanol and water Then, 1.6 g of p-toluenesulfonic a...

Embodiment 2

[0072] (1) Preparation of [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl diphenyl phosphate (I)

[0073] Dissolve 20g (S)-glycerol acetal in 300mL of dichloromethane in a three-necked flask, add 19.9g of triethylamine, drop it into an ice-water bath, dropwise add 100mL of diphenyl chlorophosphate in dichloromethane solution, keep the inside Warm reaction for 2h. TLC monitored the complete reaction of the raw materials, the reaction solution was washed with 150 mL of 1M HCl, and then washed twice with 150 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain [(R)-2,2-dimethyl-1,3- Dioxolane-4-yl]methyl diphenyl phosphate (I) 47.4 g, the yield was 86%.

[0074] (2) Preparation of (R)-2,3-dihydroxypropyl diphenyl phosphate (II)

[0075] In a three-necked flask, dissolve 20 g of [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl diphenyl phosphate (I) in 160 mL of dioxane and water 1.6 g of p-toluenesulfonic acid monohydrate was then added to t...

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Abstract

The invention provides a preparation method of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine, which comprises the following specific steps: step S1, carrying out nucleophilic substitution reaction on (S)-glyceryl acetonide and diphenyl chlorophosphate under the action of first alkali to obtain [(R)-2, 2-dimethyl-1, 3-dioxolane-4-yl] diphenyl methyl phosphate, and carrying out condensation reaction on the [(R)-2, 2-dimethyl-1, 3-dioxolane-4-yl] diphenyl methyl phosphate under the action of second alkali to obtain [(R)-2, 2-dimethyl-1, 3-dioxolane-4-yl] diphenyl methyl phosphate; s2, carrying out a ring-opening reaction on the [(R)-2, 2-dimethyl-1, 3-dioxolane-4-yl] diphenyl methyl phosphate under the action of a first acid, so as to obtain (R)-2, 3-dihydroxypropyl diphenyl phosphate, and carrying out a ring-opening reaction on the [(R)-2, 2-dimethyl-1, 3-dioxolane-4-yl] diphenyl methyl phosphate under the action of a second acid, so as to obtain (R)-2, 3-dihydroxypropyl diphenyl phosphate; s3, the (R)-2, 3-dihydroxypropyl diphenyl phosphate and oleic acid are subjected to a condensation reaction under the action of a condensing agent, and 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate is obtained; and step S4, enabling the 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate to react with ethanolamine under the action of a second alkali, and then, carrying out hydrolysis under an acidic condition, so as to obtain the 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to a preparation method of 1,2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV). Background technique [0002] Phosphatidylethanolamine, or PE for short, is the second most abundant phospholipid compound, widely found in egg yolks and soybeans and other animals and plants containing phospholipid compounds, and has a variety of biological functions. Due to its unique physicochemical properties due to its hydrophilic and lipophilic amphiphilic functional structure, it is used in the field of pharmaceutical preparations and is used in clinical practice as a drug carrier. [0003] 1,2-Dioleoyl-SN-glycerol-3-phosphorylethanolamine (DOPE), also known as dioleoylphosphatidylethanolamine, can prepare plasma-stable liposomes. DOPE is a commonly used co-phospholipid and has a strong synergistic effect in the preparation of cationic liposomes. Cationic liposomes can effectivel...

Claims

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Application Information

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IPC IPC(8): C07F9/10
CPCC07F9/106
Inventor 李晓林朱奕帆王子安刘天柱刘炼骆浩罗宇李嘉莹
Owner SUZHOU HIGHFINE BIOTECH
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