Synthesis method of oleoyl lysophosphatidyl ethanolamine

Abstract

The invention provides a synthesis method of oleoyl lysophosphatidyl ethanolamine. The synthesis method comprises the following steps: S1, reacting a compound I with phosphorus oxychloride to generate a compound II; s2, enabling the compound II to react with ethanolamine to generate a compound III; s3, the compound III is subjected to a ring-opening reaction in the presence of acid, and a compound IV is obtained; s4, the compound IV reacts with a hydrogen fluoride pyridine solution, and oleoyl lysophosphatidyl ethanolamine is generated. According to the synthesis method disclosed by the embodiment of the invention, the simple compound I is adopted as a starting raw material, the oleoyl lysophosphatidyl ethanolamine (O-LysoPE) can be obtained through three times of substitution reaction and one time of hydrolysis reaction in sequence, the synthesis route is short, the operation is simple and convenient, the yield is high, and the synthesis method is suitable for industrial production; furthermore, according to the synthesis method provided by the invention, the amino group does not need to be protected and deprotected, and the use of expensive reagents is not involved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of compound synthesis, and more particularly relates to a synthesis method of oleoyl lysophosphatidyl ethanolamine. BACKGROUND

[0002] The structure of liposomes is extremely similar to that of cell membranes, so liposomes have high biocompatibility and biodegradability. Therefore, liposomes can protect drugs from being degraded by enzymes before reaching the lesion site. Meanwhile, the drugs are "hidden" in the liposome interior in the form of physical encapsulation, which can improve drug stability, reduce drug toxicity, increase drug dosage, and achieve better therapeutic effect.

[0003] Lysophosphatidyl ethanolamine (LPE) is a kind of liposome generated by phospholipase A2 hydrolysis of phospholipid membranes. LPE can enter cells through LPE transporters on the cell membrane and participate in cell signal transduction. LPE naturally exists in animal cells or plant cells and is also present in small amounts in human serum. From the molecular structure, LPE has hydrophilic and hydrophobic groups of phosphatidyl ethanolamine. The reduction of the hydrophobic group greatly improves its hydrophilic performance, so it has good emulsion stability, antibacterial and antioxidant capacity. LPE has important medical application value and is widely used in the functional food and medical health industries.

[0004] The known literature reports the synthesis method as shown in the following formula:

[0005]

[0006] As shown in the above formula, the synthesis route is to condense glycerol acetone with oleic acid, then hydrolyze to obtain a first intermediate, then obtain a second intermediate by protecting the TBS protecting group of the hydroxyl group at position 2 of the first intermediate, and finally react the second intermediate with phosphorus oxychloride and ethanolamine to obtain the final product. However, the entire route has problems such as poor selectivity, many by-products, the need for multiple column purification, and low yield, which is not suitable for mass production. SUMMARY

[0007] Therefore, the purpose of the present application is to provide a synthesis method of oleoyl lysophosphatidyl ethanolamine with a short route, simple operation, low cost, and high yield.

[0008] To solve the above technical problems, the present application adopts the following technical solutions:

[0009] The synthesis method of oleoyl lysophosphatidyl ethanolamine according to the embodiment of the present application has a synthesis route as shown in the following formula (1):

[0010]

[0011] Specifically includes the following steps:

[0012] Step S1, react compound I with phosphorus oxychloride to generate compound II, wherein the structural formula of compound I is shown as I in formula (1), and the structural formula of compound II is shown as II in formula (1);

[0013] Step S2, reacting compound II with ethanolamine to generate compound III, the structural formula of which is shown as III in formula (1);

[0014] Step S3, the compound III undergoes a ring-opening reaction in the presence of an acid to obtain compound IV, the structural formula of which is shown as IV in formula (1);

[0015] Step S4 involves reacting compound IV with a pyridine hydrogen fluoride solution to generate oleoyl lysophosphatidylethanolamine, the structure of which is shown as V in formula (1).

[0016] According to some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent in the presence of a first base under an argon protective atmosphere.

[0017] The first solvent is dichloromethane, tetrahydrofuran, or a mixture thereof.

[0018] The first base is one or more of triethylamine, N,N-diisopropylethylamine, and pyridine.

[0019] The molar ratio of compound I: phosphorus oxychloride: the first base is 1:(1.1-1.3):(1.1-1.3).

[0020] According to some embodiments of the present invention, step S1 includes:

[0021] Phosphorus oxychloride is dissolved in tetrahydrofuran, and the first base is added thereto;

[0022] Under argon protection and in an ice-water bath, a tetrahydrofuran solution of compound I is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound II.

[0023] Furthermore, step S1 also includes:

[0024] After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound II.

[0025] According to some embodiments of the present invention, the reaction in step S2 is carried out in the second solvent in the presence of the second base under an argon protective atmosphere.

[0026] The second solvent is dichloromethane, tetrahydrofuran, or a mixture thereof.

[0027] The second base is one or more of triethylamine, N,N-diisopropylethylamine, and pyridine.

[0028] The molar ratio of compound II: ethanolamine: second base is 1:(1.0-1.3):(2.0-2.6).

[0029] According to some embodiments of the present invention, step S2 includes:

[0030] The compound II was dissolved in tetrahydrofuran;

[0031] Under argon protection and in an ice-water bath, a tetrahydrofuran solution containing compound II and triethylamine is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound III.

[0032] Furthermore, step S2 also includes:

[0033] After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound III.

[0034] According to some embodiments of the present invention, in step S3, the acid is selected from acetic acid, hydrochloric acid, or a mixture thereof, the reaction is carried out in a third solvent, the third solvent being selected from methanol, isopropanol, or a mixture thereof, the reaction temperature is 20–60°C, the reaction time is 12–20 hours, and the molar ratio of compound III to acid is 1:(1.5–3.0).

[0035] According to some embodiments of the present invention, in step S3, after the reaction is completed, n-heptane is added for extraction, the solvent is evaporated, and the mixture is passed through a chromatography column to obtain compound IV.

[0036] According to some embodiments of the present invention, step S4 includes:

[0037] Compound IV and a solution of pyridine hydrogen fluoride were added to a fourth solvent and reacted at 20–60°C for 12–20 hours to generate the oleoyl lysophosphatidylethanolamine.

[0038] After the reaction was complete, pyridine was added to adjust the pH of the reaction solution to neutral, the solvent was evaporated to dryness, and the solution was passed through a chromatography column to obtain the oleoyl lysophosphatidylethanolamine.

[0039] The fourth solvent is dichloromethane, methanol, or a mixture thereof.

[0040] The molar ratio of compound IV to pyridine is 1:(1.5 to 3.0).

[0041] The above-described technical solution of the present invention has at least one of the following beneficial effects:

[0042] According to the synthesis method of the present invention, using a simple compound I as the starting material, oleoyl lysophosphatidylethanolamine (O-LysoPE) can be obtained by sequentially undergoing 3 substitution reactions and 1 hydrolysis reaction. The synthesis route is short, easy to operate, and has a high yield, with an overall yield of up to 58%, making it suitable for industrial production.

[0043] Furthermore, according to the synthesis method of the present invention, phosphorus oxychloride is used as the phosphorylation reagent, avoiding the use of expensive phosphorylation reagents such as bis(diisopropylamino)(2-cyanoethoxy)phosphine, resulting in low cost. Moreover, it avoids the process of using peroxide to oxidize its trivalent phosphorus to pentavalent phosphorus when using bis(diisopropylamino)(2-cyanoethoxy)phosphine as the phosphorylation reagent, thereby avoiding the use of more dangerous oxidizing reagents, reducing experimental risks, and increasing experimental safety.

[0044] Furthermore, the synthesis method according to the present invention utilizes the self-protection of ethanolamine, eliminating the need for amino protection and deprotection, simplifying the operation and making the conditions easy to control. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0046] The method for synthesizing oleoyl lysophosphatidylethanolamine according to embodiments of the present invention will be described in detail below.

[0047] The synthesis method of oleoyl lysophosphatidylethanolamine according to an embodiment of the present invention is shown in the following formula (1).

[0048]

[0049] Specifically, it includes the following steps:

[0050] Step S1, react compound I with phosphorus oxychloride to generate compound II, wherein the structural formula of compound I is shown as I in formula (1), and the structural formula of compound II is shown as II in formula (1);

[0051] Step S2, reacting compound II with ethanolamine to generate compound III, the structural formula of which is shown as III in formula (1);

[0052] Step S3, the compound III undergoes a ring-opening reaction in the presence of an acid to obtain compound IV, the structural formula of which is shown as IV in formula (1);

[0053] Step S4 involves reacting compound IV with a pyridine hydrogen fluoride solution to generate oleoyl lysophosphatidylethanolamine, the structure of which is shown as V in formula (1).

[0054] In other words, according to the synthesis method of this application, starting with compound I, the target product oleoyl lysophosphatidylethanolamine is obtained after undergoing three substitution reactions and one hydrolysis reaction. In step S2, the intermediate compound II is used to form a temporary protecting group by cyclization with ethanolamine, thus eliminating the need for additional protection and deprotection of the amino group. This makes the operation simpler and easier, and more suitable for industrial-scale production.

[0055] The following will explain each step in detail.

[0056] (i) React compound I with phosphorus oxychloride to generate compound II, wherein the structural formula of compound I is shown as I in formula (1) and the structural formula of compound II is shown as II in formula (1).

[0057] In other words, the synthesis method of the present invention uses compound I as the starting material and first reacts it with phosphorus oxychloride to generate compound II.

[0058] The first solvent can be, for example, dichloromethane, tetrahydrofuran, or a mixture thereof. Tetrahydrofuran is preferred because it has good solubility, and the byproducts generated in the reaction have poor solubility in tetrahydrofuran and can be removed by filtration.

[0059] Furthermore, the first base is triethylamine, N,N-diisopropylethylamine, pyridine, etc. Preferably, the first base can be, for example, triethylamine. Triethylamine has strong basicity and low price. The molar ratio of compound I to the first base can be, for example, 1:(1.1 to 1.3). A slight excess of base allows compound I to react completely without excessive waste.

[0060] In some embodiments of the present invention, step S1 includes:

[0061] Phosphorus oxychloride is dissolved in tetrahydrofuran, and the first base is added thereto;

[0062] Under argon protection and in an ice-water bath, a tetrahydrofuran solution of compound I is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound II.

[0063] Preferably, the reaction time is 6 hours and the reaction temperature is 5-10°C. At this temperature, the raw materials are basically reacted within 4 hours. In addition, at a lower temperature, there are fewer reaction by-products and other impurities.

[0064] Furthermore, step S1 may also include:

[0065] After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound II.

[0066] In other words, compound II has simple and low post-processing, and can be used for subsequent oxidation reactions after simple treatment, generating little waste, making it very suitable for industrial production.

[0067] Post-processing removes impurities (including byproducts and reaction residues), which can prevent the introduction of unnecessary side reactions in subsequent steps, improve yield, and simplify the post-processing of intermediates.

[0068] (ii) React the compound II with ethanolamine to generate compound III, the structural formula of which is shown in formula (1) III.

[0069] As shown in formula (1), compound II, as an intermediate, undergoes a ring-closing reaction under the action of ethanolamine, which introduces an amino group and provides temporary protection for the amino group. Subsequent protection and deprotection of the amino group are not required, making the operation simpler and easier.

[0070] In some embodiments of the present invention, the reaction in step S2 is carried out in a second solvent in the presence of a second base under an argon protective atmosphere.

[0071] The second solvent is dichloromethane, tetrahydrofuran, or a mixture thereof. Preferably, the second solvent is tetrahydrofuran. Since the reaction byproducts are insoluble in tetrahydrofuran, impurities can be directly filtered off after the reaction, making the operation convenient.

[0072] The second alkali is one or more selected from triethylamine, N,N-diisopropylethylamine, and pyridine. Triethylamine is preferred. Triethylamine has strong basicity and low price. It should be noted that the first and second alkalis can be the same or different. Considering factors such as raw material management, recovery, and usage costs, it is preferable to use triethylamine for both the first and second alkalis.

[0073] The molar ratio of compound II: ethanolamine: second base is 1:(1.0-1.3):(2.0-2.6). A slight excess of ethanolamine and the second base ensures complete reaction of compound II without excessive waste. Furthermore, ethanolamine and the second base are easier to recover and process compared to compound II.

[0074] In some embodiments of the present invention, step S2 includes:

[0075] The compound II was dissolved in tetrahydrofuran;

[0076] Under argon protection and in an ice-water bath, a tetrahydrofuran solution containing compound II and triethylamine is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound III.

[0077] Preferably, the reaction temperature is 5-10°C, and the preferred reaction time is 2 hours. This reaction is relatively rapid, and the formation of impurities can be reduced at low temperatures.

[0078] In some embodiments of the present invention, step S2 further includes:

[0079] After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound III.

[0080] Post-processing is simple and easy to operate.

[0081] (iii) Step S3, cause compound III to undergo a ring-opening reaction in the presence of acid to obtain compound IV, the structural formula of which is shown in formula (1) as IV.

[0082] In other words, after obtaining compound III, it undergoes a ring-opening reaction under acidic conditions to generate compound IV.

[0083] In some embodiments of the present invention, the acid is selected from acetic acid, hydrochloric acid, or mixtures thereof, and the reaction is carried out in a third solvent.

[0084] The third solvent may be selected from methanol, isopropanol, or mixtures thereof, preferably methanol. Methanol has a high boiling point, and the higher temperature can significantly shorten the reaction time.

[0085] The reaction temperature is 20–60°C, and the reaction time is 12–20 hours. Preferably, the reaction temperature is 60°C, and the reaction time is 6 hours. Higher temperatures can significantly shorten the reaction time.

[0086] Furthermore, the molar ratio of compound III to acid can be 1:(1.5 to 3.0). An excess of acid ensures complete hydrolysis of compound III without damaging its structure.

[0087] Further, in step S3, after the reaction is complete, n-heptane is added for extraction, the solvent is evaporated, and the mixture is passed through a chromatography column to obtain compound IV.

[0088] (iv) Step S4, reacting the compound IV with a pyridine hydrogen fluoride solution to generate oleoyl lysophosphatidylethanolamine, the structure of which is shown as V in formula (1).

[0089] In other words, the target compound, oleoyl lysophosphatidylethanolamine, is finally obtained by hydrolyzing compound IV.

[0090] In some embodiments of the present invention, step S4 includes:

[0091] Compound IV and a solution of pyridine hydrogen fluoride were added to a fourth solvent and reacted at 20–60°C for 12–20 hours to generate the oleoyl lysophosphatidylethanolamine.

[0092] After the reaction was completed, pyridine was added to adjust the pH of the reaction solution to neutral, the solvent was evaporated to dryness and the solution was passed through a chromatography column to obtain the oleoyl lysophosphatidylethanolamine.

[0093] The fourth solvent can be dichloromethane, methanol, or a mixture thereof. Preferably, the fourth solvent is methanol. Methanol has a high boiling point, and a higher temperature can significantly shorten the reaction time.

[0094] Furthermore, preferably, the hydrolysis reaction is carried out at a temperature of 60°C for a time of 6 hours. Higher temperatures can significantly shorten the reaction time.

[0095] The molar ratio of compound IV to pyridine is 1:(1.5 to 3.0).

[0096] Further, in step S3, after the reaction is complete, pyridine is added to adjust the reaction solution to neutral, the solvent is evaporated and the solution is passed through a chromatography column to obtain the oleoyl lysophosphatidylethanolamine.

[0097] In other words, according to the synthesis method of the present invention, purification by chromatography is only required in the last step, and the post-processing of all intermediates is relatively simple and easy to operate, with low cost and little waste, making it very suitable for industrial-scale production.

[0098] The synthesis method of oleoyl lysophosphatidylethanolamine of the present invention will be further described in detail below through specific embodiments.

[0099] Examples 1 and 2 correspond to step S1; examples 3 and 4 correspond to step S2; examples 5 and 6 correspond to step S3; and examples 7 and 8 correspond to step S4. It should be noted that examples of different steps can be combined arbitrarily. That is, examples 1, 4, 5, and 7 can be combined to form a complete synthetic embodiment, and examples 2, 4, 6, and 8 can also be combined to form a complete synthetic embodiment, and so on, without further enumeration.

[0100] Example 1: Synthesis of Compound II

[0101] Add 48.8g of phosphorus oxychloride, 300mL of tetrahydrofuran and 11.8g of triethylamine to a 1L three-necked flask. Protect the system with argon gas, lower it into an ice-water bath and stir. Add 50.0g of compound I dissolved in 200mL of tetrahydrofuran dropwise. Control the temperature at 5-10℃ and react for 4 hours.

[0102] The reaction progress was monitored by TLC, and the reaction was processed after completion. The solvent was evaporated after filtration through diatomaceous earth to obtain 54.9 g of compound II, with a yield of 88%.

[0103] Example 2: Synthesis of Compound II

[0104] Add 48.8g of phosphorus oxychloride, 300mL of tetrahydrofuran and 10.4g of triethylamine to a 1L three-necked flask. Protect the system with argon gas, lower it into an ice-water bath and stir. Add 50.0g of compound I dissolved in 200mL of tetrahydrofuran dropwise. Control the temperature at 5-10℃ and react for 4 hours.

[0105] The reaction progress was monitored by TLC, and the reaction was processed after completion. The solvent was evaporated after filtration through diatomaceous earth to obtain 44.9 g of compound II, with a yield of 72%.

[0106] Example 3: Synthesis of Compound III

[0107] Add 50g of compound II and 400mL of tetrahydrofuran to a 1L single-necked flask. Under argon protection, place the flask in an ice-water bath with stirring. While maintaining the temperature at 10℃, add dropwise a mixed solution of 5.7g of ethanolamine and 18.9g of triethylamine dissolved in 100mL of tetrahydrofuran. Let the reaction proceed for 2 hours.

[0108] The reaction progress was monitored by TLC, and the reaction was processed after completion. The solvent was evaporated after filtering with diatomaceous earth, and 45.0 g of compound III was obtained by evaporation, with a yield of 92%.

[0109] Example 4: Synthesis of Compound III

[0110] Add 50g of compound II and 400mL of tetrahydrofuran to a 1L single-necked flask. Under argon protection, place the flask in an ice-water bath with stirring. While maintaining the temperature at 10℃, add dropwise a mixed solution of 5.7g of ethanolamine and 17.2g of triethylamine dissolved in 100mL of tetrahydrofuran. Let the reaction proceed for 2 hours.

[0111] The reaction progress was monitored by TLC, and the reaction was processed after completion. The solvent was evaporated after filtering with diatomaceous earth, and 36.7 g of compound III was obtained by evaporation, with a yield of 75%.

[0112] Example 5: Synthesis of Compound IV

[0113] Add 50g of compound III, 100mL of 50% acetic acid and 200mL of methanol to a 500mL single-necked flask, protect the system with argon, heat to 60℃ and react for 6 hours.

[0114] The reaction progress was monitored by TLC, and the product was processed after the reaction was completed. 300 mL of n-heptane was added to extract the product, the solvent was evaporated to dryness, and the product was purified by column chromatography to obtain 42.3 g of compound IV, with a yield of 82%.

[0115] Example 6: Synthesis of Compound IV

[0116] Add 50g of compound III, 100mL of 50% acetic acid and 200mL of isopropanol to a 500mL single-necked flask, protect the system with argon, heat to 60℃ and react for 6 hours.

[0117] The reaction progress was monitored by TLC, and the product was processed after the reaction was completed. 300 mL of n-heptane was added to extract the product, the solvent was evaporated to dryness, and the product was purified by column chromatography to obtain 32.0 g of compound IV, with a yield of 62%.

[0118] Example 7: Synthesis of compound V, namely oleoyl lysophosphatidylethanolamine (O-LysoPE)

[0119] Add 50g of compound III, 500mL of dichloromethane, and 3.6g of pyridine hydrogen fluoride solution (70%) to a 1L single-necked flask, and react at 30°C for 10 hours.

[0120] The reaction progress was monitored by TLC. After the reaction was completed, pyridine was added to adjust the reaction solution to neutral. The solvent was evaporated and the solution was passed through a chromatography column to obtain 32.7 g of compound V, with a yield of 81%.

[0121] The NMR data of the product are shown below:

[0122] 1H NMR (CDCl3, 400MHz): δ = 0.86-0.89 (t, 3H), 1.27-1.30 (m, 20H), 1.6 (s, 2H), 2.0-2.01 (s, 4H) ,2.3-2.34(t,2H),3.2(s,2H),3.9-4.1(m,4H),5.30-5.38(m,2H),5.55(s,1H),8.36(s,2H).

[0123] The results showed that its structure was similar to that of oleoyl lysophosphatidylethanolamine.

[0124] Example 8 Synthesis of compound V, namely oleoyl lysophosphatidylethanolamine (O-LysoPE): 50 g of compound III, 500 mL of methanol, and 3.6 g of pyridine hydrogen fluoride solution (70%) were added to a 1 L single-necked flask and reacted at 40 °C for 6 hours.

[0125] The reaction progress was monitored by TLC. After the reaction was completed, pyridine was added to adjust the reaction solution to neutral. The solvent was evaporated and the solution was passed through a chromatography column to obtain 35.1 g of compound V, with a yield of 87%.

[0126] The NMR data of the product are shown below:

[0127] 1H NMR (CDCl3, 400MHz): δ = 0.86-0.89 (t, 3H), 1.27-1.30 (m, 20H), 1.6 (s, 2H), 2.0-2.01 (s, 4H) ,2.3-2.34(t,2H),3.2(s,2H),3.9-4.1(m,4H),5.30-5.38(m,2H),5.55(s,1H),8.36(s,2H).

[0128] The results showed that its structure was similar to that of oleoyl lysophosphatidylethanolamine.

[0129] In summary, the method for synthesizing an oleoyl lysophosphatidylethanolamine of the present invention has the advantages of a short synthetic route, simple operation, low cost, and high yield.

[0130] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing oleoyl lysophosphatidylethanolamine, characterized in that, Its synthesis route is shown in equation (1) below: Specifically, the steps include the following: Step S1, react compound I with phosphorus oxychloride to generate compound II, wherein the structural formula of compound I is shown as I in formula (1), and the structural formula of compound II is shown as II in formula (1); Step S2, reacting compound II with ethanolamine to generate compound III, the structural formula of which is shown as III in formula (1); Step S3, the compound III undergoes a ring-opening reaction in the presence of an acid to obtain compound IV, the structural formula of which is shown as IV in formula (1); Step S4 involves reacting compound IV with a pyridine hydrogen fluoride solution to generate oleoyl lysophosphatidylethanolamine, the structure of which is shown as V in formula (1).

2. The synthesis method according to claim 1, characterized in that, The reaction in step S1 is carried out in the first solvent in the presence of the first base under an argon protective atmosphere. The first solvent is dichloromethane, tetrahydrofuran, or a mixture thereof. The first base is one or more of triethylamine, N,N-diisopropylethylamine, and pyridine. The molar ratio of compound I: phosphorus oxychloride: the first base is 1:(1.1-1.3):(1.1-1.3).

3. The synthesis method according to claim 2, characterized in that, Step S1 includes: Phosphorus oxychloride is dissolved in tetrahydrofuran, and the first base is added thereto; Under argon protection and in an ice-water bath, a tetrahydrofuran solution of compound I is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound II.

4. The synthesis method according to claim 3, characterized in that, Step S1 further includes: After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound II.

5. The synthesis method according to claim 1, characterized in that, The reaction in step S2 is carried out in the second solvent in the presence of the second base under an argon protective atmosphere. The second solvent is dichloromethane, tetrahydrofuran, or a mixture thereof. The second base is one or more of triethylamine, N,N-diisopropylethylamine, and pyridine. The molar ratio of compound II: ethanolamine: second base is 1:(1.0-1.3):(2.0-2.6).

6. The synthesis method according to claim 5, characterized in that, Step S2 includes: The compound II was dissolved in tetrahydrofuran; Under argon protection and in an ice-water bath, a tetrahydrofuran solution containing compound II and triethylamine is added dropwise while stirring, and the reaction is carried out at 0–30°C for 2–6 hours to generate compound III.

7. The synthesis method according to claim 6, characterized in that, Step S2 further includes: After the reaction was completed, the diatomaceous earth was filtered and the solvent was evaporated to obtain compound III.

8. The synthesis method according to claim 1, characterized in that, In step S3, the acid is selected from acetic acid, hydrochloric acid, or a mixture thereof, the reaction is carried out in a third solvent, the third solvent is selected from methanol, isopropanol, or a mixture thereof, the reaction temperature is 20-60°C, the reaction time is 12-20 hours, and the molar ratio of compound III to acid is 1:(1.5-3.0).

9. The synthesis method according to claim 8, characterized in that, In step S3, after the reaction is complete, n-heptane is added for extraction, the solvent is evaporated, and the mixture is passed through a chromatography column to obtain compound IV.

10. The synthesis method according to claim 1, characterized in that, Step S4 includes: Compound IV and a solution of pyridine hydrogen fluoride were added to a fourth solvent and reacted at 20–60°C for 12–20 hours to generate the oleoyl lysophosphatidylethanolamine. After the reaction was complete, pyridine was added to adjust the pH of the reaction solution to neutral, the solvent was evaporated to dryness, and the solution was passed through a chromatography column to obtain the oleoyl lysophosphatidylethanolamine. The fourth solvent is dichloromethane, methanol, or a mixture thereof, and the molar ratio of compound IV to pyridine is 1:(1.5 to 3.0).

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