CN114853806B - Preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine - Google Patents

Preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine Download PDF

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CN114853806B
CN114853806B CN202210681395.0A CN202210681395A CN114853806B CN 114853806 B CN114853806 B CN 114853806B CN 202210681395 A CN202210681395 A CN 202210681395A CN 114853806 B CN114853806 B CN 114853806B
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CN114853806A (en
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李晓林
朱奕帆
王子安
刘天柱
刘炼
骆浩
罗宇
李嘉莹
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Suzhou Highfine Biotech Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/10—Phosphatides, e.g. lecithin
    • C07F9/106—Adducts, complexes, salts of phosphatides

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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, nucleophilic substitution reaction is carried out on (S) -glycerylacetone and diphenyl chlorophosphate under the action of first alkali, so as to obtain [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate; s2, ring-opening reaction is carried out on the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate under the action of first acid, so as to obtain (R) -2, 3-dihydroxypropyl diphenyl phosphate; step S3, enabling the (R) -2, 3-dihydroxypropyl diphenyl phosphate and oleic acid to undergo condensation reaction under the action of a condensing agent to obtain 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate; and S4, reacting the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate with ethanolamine under the action of a second base, and then hydrolyzing under an acidic condition to obtain the 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine.

Description

Preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine
Technical Field
The invention relates to the technical field of compound preparation, in particular to a preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine (IV).
Background
Phosphatidylethanolamine, abbreviated as PE, has a second content in phospholipid compounds, and is widely used in animals and plants containing phospholipid compounds such as egg yolk and soybean, and has various biological functions. The hydrophilic and lipophilic amphiphilic functional structure has unique physicochemical properties, so that the hydrophilic and lipophilic amphiphilic functional structure is applied to the field of pharmaceutical preparations and is applied clinically as a pharmaceutical carrier.
1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (DOPE), also known as dioleoyl phosphatidylethanolamine, can be used to prepare plasma-stabilized liposomes. DOPE is a common phospholipid, and has strong synergistic effect in the process of preparing cationic liposome. Cationic liposome can effectively enter cells for transfection and avoid immune toxicity, is a safe and effective gene therapy vector, but the stability, membrane fusion and transfection efficiency of the liposome are generally poor under the condition of not adding auxiliary phospholipid. The DOPE can stabilize the double-layer membrane and reduce the toxicity of positive components, can assist the cell permeation of the cationic liposome and improve the transmembrane efficiency, so that the addition of the DOPE can enable the cationic liposome membrane to be fused better, have higher stability and smaller cytotoxicity. In addition, DOPE is mostly in mg grade in domestic market.
Therefore, the synthesis method which has wide development applicability and can prepare DOPE in large scale has practical significance for meeting domestic market and replacing imported products.
Disclosure of Invention
In view of the above, the invention provides a preparation method of DOPE with high stability and simple operation.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine comprises the following specific steps:
step S1, nucleophilic substitution reaction is carried out on (S) -glycerylacetone and diphenyl chlorophosphate under the action of first alkali, so as to obtain [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate;
s2, ring-opening reaction is carried out on the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate under the action of first acid, so as to obtain (R) -2, 3-dihydroxypropyl diphenyl phosphate;
step S3, enabling the (R) -2, 3-dihydroxypropyl diphenyl phosphate and oleic acid to undergo condensation reaction under the action of a condensing agent to obtain 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate;
and S4, reacting the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate with ethanolamine under the action of a second base, and then hydrolyzing under an acidic condition to obtain the 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine.
Further, in the step S1, the first base is one or more selected from pyridine, triethylamine, DIEA, sodium carbonate, and sodium hydroxide.
Further, in the step S1, the molar ratio of the (S) -glycerol formal, the diphenyl chlorophosphate and the first base is 1 (1-1.5): 1-1.8; the reaction temperature is 0-35 ℃ and the reaction time is 1-10 hours.
Further, in the step S2, the first acid is one or more selected from hydrochloric acid, acetic acid, p-toluenesulfonic acid monohydrate, and trifluoroacetic acid.
Further, in the step S2, the molar ratio of the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate and the first acid is 1 (0.05-2), the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours.
Further, in the step S3, the condensing agent is one or more selected from N, N '-Dicyclohexylcarbodiimide (DCC) and N, N' -Diisopropylcarbodiimide (DIC).
Further, in the step S3, the condensation reaction is performed under the action of a catalyst, wherein the catalyst is p-dimethylaminopyridine.
Further, in the step S3, the molar ratio of the (R) -2, 3-dihydroxypropyl diphenyl phosphate, the oleic acid, the condensing agent and the catalyst is 1 (1.8-2.3): (0.01-0.1); the reaction temperature is 0-40 ℃ and the reaction time is 4-20 hours.
Further, in the step S4, the second base is one or more selected from pyridine, triethylamine, diethylamine, N-Diisopropylethylamine (DIEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
Further, in the step S4, the mole ratio of the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III), the ethanolamine and the second base is 1 (1-1.3): 1-3, the reaction temperature is 0-45 ℃, and the reaction time is 8-25 hours.
Further, step S1 may be performed in a first reaction solvent which is dichloromethane, toluene, n-hexane, DMF or acetonitrile; step S2 may be performed in a second reaction solvent, which is any one of methanol, ethanol, tetrahydrofuran, dioxane, and a mixed solvent thereof with water; step S3 may be performed in a third reaction solvent, which is tetrahydrofuran, acetonitrile, dichloromethane or chloroform; step S4 may be performed in a fourth reaction solvent, which is dichloromethane, chloroform, or tetrahydrofuran.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method provided by the embodiment of the invention, chiral glycerol acetonide reacts with diphenyl chlorophosphate, is hydrolyzed and then is spliced with oleic acid to obtain dioleoyl phosphate, and finally is spliced with ethanolamine to construct phospholipid head group, so that DOPE is obtained. The DOPE can be obtained through four steps of reactions, the route is short, and the synthesis cost is low.
In addition, the raw materials and the auxiliary materials related to the preparation method are low in price and easy to obtain, the experimental safety is high, the steps are few, the operation is simple and convenient, and the conditions are easy to control.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The following first describes in bulk a method of preparing DOPE according to an embodiment of the present invention.
The preparation method of DOPE according to the embodiment of the invention comprises the following steps:
step S1, nucleophilic substitution reaction is carried out on (S) -glycerylacetone and diphenyl chlorophosphate under the action of first alkali, thus obtaining [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate.
Specifically, the reaction formula is represented by the following formula (1):
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 preferable, and the reaction yield is higher.
Further, in the step S1, the molar ratio of the (S) -glycerol formal, the diphenyl chlorophosphate and the first base is 1 (1-1.5): 1-1.8; the reaction temperature is 0-35 ℃ and the reaction time is 1-10 hours. Preferably, the molar ratio of the (S) -glycerol formal, diphenyl chlorophosphate and the base is 1:1.0:1.3. The reaction temperature is preferably 0 to 10℃and the occurrence of side reactions can be reduced.
Further, step S1 may be performed in a first reaction solvent which is dichloromethane, toluene, n-hexane, DMF or acetonitrile. Among them, methylene chloride is particularly preferable, thereby reducing the generation of impurities.
Preferably, the step S1 further includes: after the reaction is completed, the mixture is washed by dilute hydrochloric acid, washed by water, dried and evaporated to dryness.
Step S2, ring-opening reaction is carried out on the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate under the action of first acid, so as to obtain (R) -2, 3-dihydroxypropyl diphenyl phosphate.
Specifically, the reaction formula is represented by the following formula (2):
further, in the step S2, the first acid is one or more selected from hydrochloric acid, acetic acid, p-toluenesulfonic acid monohydrate, and trifluoroacetic acid. Among them, p-toluenesulfonic acid monohydrate is preferable, which contributes to an acceleration of the reaction rate.
Further, in the step S2, the molar ratio of the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate and the first acid is 1 (0.05-2), the reaction temperature is 0-50 ℃, and the reaction time is 1-10 hours. Preferably, the molar ratio of the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate and the first acid is 1:0.15. The reaction temperature is preferably at normal temperature, so that occurrence of side reactions is reduced.
Further, step S2 may be performed in a second reaction solvent which is any one of methanol, ethanol, tetrahydrofuran, dioxane, and a mixed solvent thereof with water. Among them, a mixed solvent of methanol and water is preferable, which is more conducive to the reaction and improves the yield.
Preferably, in step S2, after the reaction is completed, the method further includes the steps of: adding alkali to adjust pH to neutral, evaporating to dry the solvent, pulping and purifying.
And step S3, enabling the (R) -2, 3-dihydroxypropyl diphenyl phosphate and oleic acid to undergo a condensation reaction under the action of a condensing agent to obtain 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate.
Specifically, the reaction formula is represented by the following formula (3):
further, in the step S3, the condensing agent is one or more selected from N, N '-Dicyclohexylcarbodiimide (DCC) and N, N' -Diisopropylcarbodiimide (DIC).
Further, in the step S3, the condensation reaction is performed under the action of a catalyst, wherein the catalyst is p-dimethylaminopyridine.
Further, in the step S3, the molar ratio of the (R) -2, 3-dihydroxypropyl diphenyl phosphate, the oleic acid, the condensing agent and the catalyst is 1 (1.8-2.3): (0.01-0.1); the reaction temperature is 0-40 ℃ and the reaction time is 4-20 hours. Preferably, the molar ratio of the (R) -diphenyl 2, 3-dihydroxypropyl phosphate (II), the oleic acid, the condensing agent and the catalyst is 1:2.1:2.1:0.05. The reaction temperature is preferably 0 to 10℃so as to reduce the occurrence of side reactions.
Further, step S3 may be performed in a third reaction solvent, which is tetrahydrofuran, acetonitrile, dichloromethane or chloroform. Among them, dichloromethane is preferable, which is advantageous in reducing cost and simplifying operation as compared with other solvents.
Preferably, in the step S3, after the reaction is completed, the method further includes the steps of: suction filtering, washing with dilute hydrochloric acid, washing with water, drying, and evaporating solvent.
And S4, reacting the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate with ethanolamine under the action of a second base, and then hydrolyzing under an acidic condition to obtain the 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine.
Specifically, the reaction formula is represented by the following formula (4):
further, in the step S4, the second base is one or more selected from pyridine, triethylamine, diethylamine, N-Diisopropylethylamine (DIEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Preferably, the second base is triethylamine, and other side reactions cannot occur due to the fact that the alkalinity is too strong, and the reaction effect is poor.
Further, in the step S4, the mole ratio of the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III), the ethanolamine and the second base is 1 (1-1.3): 1-3, the reaction temperature is 0-45 ℃, and the reaction time is 8-25 hours. Preferably, the molar ratio of the 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate (III), the ethanolamine and the second base is 1:1.2:2. The reaction temperature is preferably normal temperature, thereby being beneficial to reducing the occurrence of side reaction and improving the reaction yield.
Further, step S4 may be performed in a fourth reaction solvent, which is dichloromethane, chloroform, or tetrahydrofuran. Preferably, the catalyst is dichloromethane, so that the production cost can be saved.
Preferably, in step S4, after the reaction is completed, the method further includes the steps of: evaporating the solvent, pulping and purifying.
The invention can provide a simple, convenient and effective preparation method of 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine (IV), and in addition, the raw and auxiliary materials related by the preparation method are cheap and easy to obtain, the experimental safety is high, the steps are few, the operation is simple and the condition is easy to control.
The preparation method of the present invention is described in further detail below by way of specific examples.
Example 1
(1) Preparation of[ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonic acid diphenyl ester (I)
In a three-necked flask, 20g of (S) -glyceroglycol was dissolved in 300mL of methylene chloride, 15.6g of pyridine was added thereto, and the mixture was cooled to an ice-water bath, and 100mL of a diphenyl chlorophosphate methylene chloride solution was added dropwise thereto, and the internal temperature was maintained for 2 hours. TLC monitored complete reaction of the starting material, washing the reaction solution with 150mL of 1M HCl, washing twice with 150mL of clean water, drying over anhydrous sodium sulfate, concentrating under reduced pressure to give 50.7g of diphenyl [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonate (I) in 92% yield.
(2) Preparation of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II)
In a three-necked flask, 20g of diphenyl [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonate (I) was dissolved in 160mL of a mixed solvent of methanol and water, followed by addition of 1.6g of p-toluenesulfonic acid monohydrate and reaction at room temperature for 6 hours.
TLC (thin layer chromatography) detects that the raw materials are completely reacted, triethylamine is added to be neutral, the solvent is evaporated, and then mixed solvent of ethyl acetate and petroleum ether is used for pulping, so that 15.5g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) is obtained, and the yield is 87%.
(3) Preparation of 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III)
In a three-necked flask, 20g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) was dissolved in 300mL of methylene chloride, 36.6g of oleic acid and 0.4g of DMAP were added, followed by cooling to an ice-water bath, and a methylene chloride solution of 100mL of DCC was added dropwise thereto to conduct an internal temperature reaction for 7 hours.
TLC detection of the complete reaction of the raw materials, suction filtration, removal of insoluble substances, washing of the filtrate with 1M HCl, washing twice with clear water, drying with anhydrous sodium sulfate, and evaporation to dryness gave 41g of 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III) in 78% yield.
(4) Preparation of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV)
20g of diphenyl 1, 2-dioleoyl-SN-glycero-3-phosphate (III) was dissolved in 150mL of methylene chloride in a three-necked flask, and then 1.7g of ethanolamine, 4.7g of triethylamine was added thereto to react at room temperature for 8 hours. TLC showed complete reaction of starting material, concentration of dichloromethane under reduced pressure, followed by addition of 120mL of 80% aqueous acetic acid and reaction at room temperature for 8h.
TLC detection of complete reaction of the starting material, concentration under reduced pressure to remove the reaction solvent, beating with acetone, yielded 12.9g of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV) with a yield of 74%.
Example 2
(1) Preparation of[ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonic acid diphenyl ester (I)
In a three-necked flask, 20g of (S) -glyceroglycol was dissolved in 300mL of methylene chloride, 19.9g of triethylamine was added thereto, and the mixture was cooled to an ice-water bath, and 100mL of a diphenyl chlorophosphate methylene chloride solution was added dropwise thereto, and the internal temperature was maintained for 2 hours. TLC monitored complete reaction of the starting material, washing the reaction solution with 150mL of 1M HCl, washing twice with 150mL of clean water, drying over anhydrous sodium sulfate, concentrating under reduced pressure to give 47.4g of diphenyl [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonate (I) in 86% yield.
(2) Preparation of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II)
In a three-necked flask, 20g of diphenyl [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonate (I) was dissolved in 160mL of a mixed solvent of dioxane and water, followed by addition of 1.6g of p-toluenesulfonic acid monohydrate and reaction at room temperature for 6 hours.
TLC (thin layer chromatography) detects that the raw materials are completely reacted, triethylamine is added to be neutral, the solvent is evaporated, and then mixed solvent of ethyl acetate and petroleum ether is used for pulping, so that 15g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) is obtained, and the yield is 84%.
(3) Preparation of 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III)
In a three-necked flask, 20g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) was dissolved in 300mL of methylene chloride, 36.6g of oleic acid, 0.4g of DMAP was added, and the mixture was cooled down to an ice-water bath, and a methylene chloride solution of 100mL of EDCI was added dropwise thereto to carry out an internal temperature reaction for 7 hours.
TLC detection of the complete reaction of the starting materials, suction filtration, removal of insoluble material, washing of the filtrate with 1M HCl, washing twice with clear water, drying over anhydrous sodium sulfate, and evaporation to dryness gave 38.4g of 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate (III) in 73% yield.
(4) Preparation of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV)
20g of diphenyl 1, 2-dioleoyl-SN-glycero-3-phosphate (III) was dissolved in 150mL of methylene chloride in a three-necked flask, followed by addition of 1.7g of ethanolamine, 4.7g of triethylamine and reaction at 35℃for 8 hours. TLC showed complete reaction of starting material, concentration of dichloromethane under reduced pressure, followed by addition of 120mL of 80% aqueous acetic acid and reaction at 35℃for 8h.
TLC detection of complete reaction of the starting material, concentration under reduced pressure to remove the reaction solvent, beating with acetone, yielded 11.7g of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV) with a yield of 67%.
Example 3
(1) Preparation of[ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonic acid diphenyl ester (I)
In a three-necked flask, 20g of (S) -glyceroglycol was dissolved in 300mL of acetonitrile, 15.6g of pyridine was added thereto, and the mixture was cooled to an ice-water bath, and 100mL of an acetonitrile solution of diphenyl chlorophosphate was added dropwise thereto, and the internal temperature was maintained for 2 hours. TLC monitored complete reaction of starting material, reaction solution washed with 150mL 1M HCl, twice with 150mL clear water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 43.6g with a yield of 79%.
(2) Preparation of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II)
In a three-necked flask, 20g of diphenyl [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methylphosphonate (I) was dissolved in 160mL of a mixed solvent of methanol and water, followed by addition of 3.3g of acetic acid and reaction at room temperature for 6 hours.
TLC (thin layer chromatography) detects that the raw materials are completely reacted, triethylamine is added to be neutral, the solvent is evaporated, and then mixed solvent of ethyl acetate and petroleum ether is used for pulping, 13.4g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) is obtained, and the yield is 75%.
(3) Preparation of 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III)
In a three-necked flask, 20g of (R) -2, 3-dihydroxypropyl diphenyl phosphate (II) was dissolved in 300mL of methylene chloride, 34.8g of oleic acid and 0.4g of DMAP were added, followed by cooling to an ice-water bath, and a methylene chloride solution of 100mL of DCC was added dropwise thereto to conduct an internal temperature reaction for 7 hours.
TLC detection of the complete reaction of the starting materials, suction filtration, removal of insoluble material, washing of the filtrate with 1M HCl, washing twice with clear water, drying over anhydrous sodium sulfate, and evaporation to dryness gave 37.9g of 1, 2-dioleoyl-SN-glycerol-3-diphenyl phosphate (III) in 72% yield.
(4) Preparation of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV)
20g of diphenyl 1, 2-dioleoyl-SN-glycero-3-phosphate (III) was dissolved in 150mL of methylene chloride, followed by addition of 1.7g of ethanolamine, 7.1g of DBU and reaction at room temperature for 8 hours. TLC showed complete reaction of starting material, concentration of dichloromethane under reduced pressure, followed by addition of 120mL of 80% aqueous acetic acid and reaction at room temperature for 8h.
TLC detection of complete reaction of the starting material, concentration under reduced pressure to remove the reaction solvent, beating with acetone, yielded 11.2g of 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine (IV) with a yield of 64%.
As can be seen from the above examples, the method for preparing 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine (IV) has the advantages of simple operation, short route, low cost, high yield and high chiral purity.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.

Claims (6)

1. The preparation method of the 1, 2-dioleoyl-SN-glycerol-3-phosphorylethanolamine is characterized by comprising the following specific steps of:
step S1, nucleophilic substitution reaction is carried out on (S) -glycerylacetone and diphenyl chlorophosphate under the action of first alkali to obtain [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate, wherein the first alkali is one or more selected from pyridine, triethylamine, N-Diisopropylethylamine (DIEA), sodium carbonate and sodium hydroxide;
s2, ring-opening reacting the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate under the action of a first acid to obtain (R) -2, 3-dihydroxypropyl diphenyl phosphate, wherein the first acid is one or more selected from hydrochloric acid, acetic acid, p-toluenesulfonic acid monohydrate and trifluoroacetic acid;
step S3, enabling the (R) -2, 3-dihydroxypropyl diphenyl phosphate and oleic acid to undergo condensation reaction under the action of a condensing agent to obtain 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate, wherein the condensing agent is one or more selected from N, N '-Dicyclohexylcarbodiimide (DCC) and N, N' -Diisopropylcarbodiimide (DIC);
and S4, reacting the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate with ethanolamine under the action of a second base, and then hydrolyzing under an acidic condition to obtain the 1, 2-dioleoyl-SN-glycero-3-phosphorylethanolamine, wherein the second base is one or more selected from pyridine, triethylamine, diethylamine, N-diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
2. The preparation method according to claim 1, wherein in the step S1, the molar ratio of the (S) -glycerol formal, diphenyl chlorophosphate and the first base is 1 (1-1.5): 1-1.8; the reaction temperature is 0-35 ℃ and the reaction time is 1-10 hours.
3. The method according to claim 1, wherein in the step S2, the molar ratio of the [ (R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] diphenyl methylphosphonate to the first acid is 1 (0.05-2), the reaction temperature is 0-50 ℃ and the reaction time is 1-10 hours.
4. The method according to claim 1, wherein in the step S3, the condensation reaction is further performed under the action of a catalyst, and the catalyst is p-dimethylaminopyridine.
5. The preparation method according to claim 4, wherein in the step S3, the molar ratio of the (R) -2, 3-dihydroxypropyl diphenyl phosphate, the oleic acid, the condensing agent and the catalyst is 1 (1.8-2.3): 0.01-0.1; the reaction temperature is 0-40 ℃ and the reaction time is 4-20 hours.
6. The method according to claim 1, wherein in the step S4, the molar ratio of the 1, 2-dioleoyl-SN-glycero-3-diphenyl phosphate (III), the ethanolamine and the second base is 1 (1-1.3): 1-3, the reaction temperature is 0-45 ℃, and the reaction time is 8-25 hours.
CN202210681395.0A 2022-06-15 2022-06-15 Preparation method of 1, 2-dioleoyl-SN-glycerinum-3-phosphorylethanolamine Active CN114853806B (en)

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