CN114478622A - Preparation method of phosphatidylcholine - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of phosphatidylcholine. The preparation method of the phosphatidylcholine provided by the invention comprises the following steps: dissolving (R) -glycidol and a first acylation reagent in a first organic solvent, and carrying out a first acylation reaction to obtain (S) -glycidol fatty acid ester; and (S) -glycidyl fatty acid ester, phosphorylcholine and a second organic solvent are mixed for ring-opening reaction to obtain the lysophosphatidylcholine. And dissolving lysophosphatidylcholine and a second acylation reagent in a third organic solvent, and carrying out a second acylation reaction to obtain phosphatidylcholine. The method has the advantages of simple process, few reaction steps, mild reaction conditions and more convenient operation; in addition, the post-treatment method is simple and convenient, the discharge of experimental waste is reduced, and the purity of the prepared phosphatidylcholine is more than 98%, so that the method is suitable for industrial preparation.

Description

A kind of preparation method of phosphatidylcholine

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of phosphatidylcholine.

Background technique

Phosphatidylcholine widely exists in animals and plants, is the basic substance of life activities, has important physiological functions and unique emulsifying properties, and has important uses in food, health products, medicine and other industries. Medicines made with phosphatidylcholine can be used to prepare high-energy parenteral fluid-fat emulsions, carriers of various anticancer drugs and liposomes. For example, distearoyl phosphatidyl choline is one of the important excipients for the preparation of liposomes. Di erucyl phosphatidyl choline is used in the sustained-release polycystic bupivacaine liposome named Exparel. Phosphatidylcholine is used in a product called Depocyt (cytarabine) for the treatment of lymphoma meningitis. Extraction from animal and plant carriers rich in phospholipids is a traditional way to prepare phosphatidylcholine, but the substances obtained in the traditional way are mixtures, which cannot fully meet the needs of the market.

In order to obtain high-purity phosphatidylcholine with a single and clear structure-activity relationship, researchers used chemical methods to synthesize phosphatidylcholine. For example, in the literature (Synthesis of a Small Library of Mixed-Acid Phospholipids from D-Mannitol as a Homochiral Stratifying Material Chem. Pharm. Bull. 1999, 47(11) 1659-1663), a benzyl-protected chiral diol is used as the raw material, According to the purpose, two identical or different acyl groups can be connected. When introducing different acyl groups, the difference in the activity of primary and secondary hydroxyl groups can be used or the selective protective groups can be used to introduce them. Finally, the protective groups can be removed and then coupled with the phospholipid head group; the introduction of acyl groups can be carried out by using the corresponding of fatty acids, fatty acid anhydrides or more reactive acid chlorides. Another example is Chen Guang's master's thesis "Research on the Total Synthesis of Phosphatidylcholine, Phosphatidylethanolamine and Phosphatidylglycerol" of Northwestern University, using glycerol as the precursor compound, designed the total synthesis of glycerophospholipids with the same carbon chain. Route; using ketal, 3,4-dimethoxybenzyl as the protecting group of dihydroxyl and monohydroxyl of glycerol skeleton, respectively, with acetic acid aqueous solution, 2,3-dichloro-5,6-dicyanobenzoquinone ( DDQ) as the corresponding deprotection reagent; successively through the steps of reduction, chlorination, condensation, protection and deprotection of dihydroxyl and monohydroxyl, acylation, phosphorylation, head group protection, coupling and deprotection to obtain two. Stearoylphosphatidylcholine.

However, the existing route for preparing phosphatidylcholine has long steps, complicated reaction and high requirements on equipment conditions, so it is not suitable for scale-up preparation.

SUMMARY OF THE INVENTION

In view of this, the present invention provides a preparation method of phosphatidylcholine, and the preparation method provided by the present invention has simple process, convenient operation and easy industrial production.

In order to solve the above-mentioned technical problems, the invention provides a preparation method of phosphatidylcholine, comprising the following steps:

Dissolving (R)-glycidol and the first acylating agent in the first organic solvent, and carrying out the first acylation reaction to obtain (S)-glycidyl fatty acid ester;

Mixing the (S)-glycidyl fatty acid ester, phosphorylcholine and the second organic solvent, and carrying out a ring-opening reaction to obtain the lysophosphatidylcholine;

The lysophosphatidylcholine and the second acylation reagent are dissolved in the third organic solvent, and the second acylation reaction is performed to obtain the phosphatidylcholine.

Preferably, the first acylating reagent and the second acylating reagent independently comprise carboxylic acid, acid chloride or acid anhydride.

Preferably, the number of carbon atoms in the carboxylic acid, acid chloride and acid anhydride is independently 8-27.

Preferably, the carboxylic acid includes n-octanoic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, oleic acid or arachidonic acid;

The acid chloride includes fatty acid chloride, myristoyl chloride, palmitoyl chloride or stearoyl chloride;

The acid anhydride includes fatty acid anhydride, lauric anhydride, stearic anhydride or oleic anhydride.

Preferably, the molar ratio of the (R)-glycidol to the first acylating reagent is 1:1-1.8;

The temperature of the first acylation reaction is -15˜50° C.; the time of the first acylation reaction is 2˜8 h.

Preferably, the molar ratio of the lysophosphatidylcholine to the second acylating reagent is 1:1-1.8;

The temperature of the second acylation reaction is 50˜150° C.; the time of the second acylation reaction is 8˜24 h.

Preferably, the molar ratio of the phosphorylcholine to (S)-glycidyl fatty acid ester is 1:1-1.5.

Preferably, the ring-opening reaction is carried out under catalyst conditions;

The molar ratio of the phosphorylcholine and the catalyst is 1:0.1-1.

Preferably, the catalyst includes one or more of transition metal oxides, sulfuric acid, nitric acid, hydrochloric acid, cationic resin and solid superacid.

Preferably, the temperature of the ring-opening reaction is 60˜150° C.; the time of the ring-opening reaction is 12˜48 h.

The invention provides a preparation method of phosphatidylcholine, comprising the following steps: dissolving (R)-glycidol and a first acylation reagent in a first organic solvent, and performing a first acylation reaction to obtain (S)- Glycidyl fatty acid ester; mixing the (S)-glycidyl fatty acid ester, phosphorylcholine and a second organic solvent, and performing a ring-opening reaction to obtain the lysophosphatidylcholine. The lysophosphatidylcholine and the second acylation reagent are dissolved in the third organic solvent, and the second acylation reaction is performed to obtain the phosphatidylcholine. The preparation method provided by the invention has simple process, few reaction steps, convenient operation, and is suitable for industrial production. The preparation method provided by the present invention has the following benefits:

(1) According to the preparation method provided by the present invention, phosphatidylcholine with a single and clear structure can be prepared, and high-purity double fatty acid chains containing symmetrical or asymmetrical, saturated or unsaturated, substituted or unsubstituted double fatty acid chains can be prepared according to the structure-activity relationship Phosphatidylcholine.

(2) the present invention takes common (R)-glycidol, carboxylic acid, acyl chloride, acid anhydride as starting raw material, the intermediate step uses this conventional chemical of phosphorylcholine, and the solvent is a common industrial grade reagent, without further processing, It has the advantage of easy availability of raw materials.

(3) the process of the present invention is concise, the reaction steps are few, the reaction conditions are mild, and the operation is more convenient; in addition, the post-processing method is simple and convenient, reduces the discharge of experimental waste, and the prepared phosphatidylcholine is more than 98% pure, which is suitable for industrialized preparation .

Description of drawings

Fig. 1 is the ¹ H NMR spectrum of lauroyl lysophosphatidyl prepared in Example 2;

Fig. 2 is the liquid chromatogram of the lauroyl lysophosphatidylcholine prepared in Example 2;

Fig. 3 is the ¹ H NMR spectrum of dilauroylphosphatidylcholine prepared in Example 2;

Fig. 4 is the liquid chromatogram of the dilauroylphosphatidylcholine that embodiment 2 prepares;

5 is the ¹ H NMR spectrum of the myristoyl lysophosphatidylcholine prepared in Example 3;

Fig. 6 is the liquid chromatography of the myristoyl lysophosphatidylcholine prepared in Example 3;

Fig. 7 is the ¹ H NMR spectrum of dimyristoylphosphatidylcholine prepared in Example 3;

Fig. 8 is the liquid chromatogram of dimyristoyl phosphatidylcholine prepared in Example 3;

Figure 9 is the ¹ H NMR spectrum of the palmitoyl lysophosphatidylcholine prepared in Example 4;

Figure 10 is the liquid chromatogram of the palmitoyl lysophosphatidylcholine prepared in Example 4;

Figure 11 is the ¹ H NMR spectrum of dipalmitoyl phosphatidylcholine prepared in Example 4;

Fig. 12 is the liquid chromatogram of dipalmitoyl phosphatidylcholine prepared in Example 4;

Figure 13 is the ¹ H NMR chart of the stearoyl lysophosphatidylcholine prepared in Example 5;

Figure 14 is the liquid chromatogram of the stearoyl lysophosphatidylcholine prepared in Example 5;

Figure 15 is the ¹ H NMR spectrum of the distearoyl phosphatidyl choline prepared in Example 5;

Figure 16 is the liquid chromatogram of the distearoyl phosphatidylcholine prepared in Example 5;

Figure 17 is the ¹ H NMR spectrum of dioleoylphosphatidylcholine prepared in Example 7;

Figure 18 is the liquid chromatogram of dioleoylphosphatidylcholine prepared in Example 7;

Figure 19 is the ¹ H NMR spectrum of 1-stearoyl-2-palmitoylphosphatidylcholine prepared in Example 10;

20 is a liquid chromatogram of 1-stearoyl-2-palmitoylphosphatidylcholine prepared in Example 10.

Detailed ways

The invention provides a preparation method of phosphatidylcholine, comprising the following steps:

Dissolving (R)-glycidol and the first acylating agent in the first organic solvent, and carrying out the first acylation reaction to obtain (S)-glycidyl fatty acid ester;

The (S)-glycidyl fatty acid ester, phosphorylcholine and the second organic solvent are mixed to carry out a ring-opening reaction to obtain the lysophosphatidylcholine.

The lysophosphatidylcholine and the second acylation reagent are dissolved in the third organic solvent, and the second acylation reaction is performed to obtain the phosphatidylcholine.

In the present invention, (R)-glycidol and the first acylating agent are dissolved in the first organic solvent, and the first acylation reaction is carried out to obtain (S)-glycidyl fatty acid ester. In the present invention, the first acylating reagent preferably includes carboxylic acid, acid chloride or acid anhydride, more preferably carboxylic acid or acid anhydride. In the present invention, the number of carbon atoms in the carboxylic acid, acid chloride and acid anhydride independently is preferably 8-27, more preferably 10-26. In the present invention, the carboxylic acid preferably has the structure shown in formula a-1; the acid chloride preferably has the structure shown in a-2; the acid anhydride preferably has the structure shown in formula a-3;

Among them, R ¹ is preferably a C7-C26 alkyl group or a substituted alkyl group, and more preferably a C7-C26 alkyl group. In the present invention, the carboxylic acid preferably includes fatty acid, n-octanoic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, oleic acid or arachidonic acid, more preferably arachidic acid, oleic acid, or arachidonic acid acid. In the present invention, the acid chloride preferably includes fatty acid chloride, myristoyl chloride, palmitoyl chloride or stearoyl chloride, more preferably myristoyl chloride or stearoyl chloride. In the present invention, the acid anhydride preferably includes fatty acid anhydride, lauric anhydride, stearic anhydride or oleic anhydride, more preferably lauric anhydride or oleic anhydride.

In the present invention, the first organic solvent preferably includes acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether , one or more of dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, toluene and xylene, more preferably 1,4-dioxane, dichloromethane or toluene. In the present invention, when the first organic solvent is two or more of the above-mentioned specific substances, the present invention does not specifically limit the proportion of the specific substances, and any proportion may be used.

In the present invention, the molar ratio of the (R)-glycidol to the first acylating agent is preferably 1:1-1.8, more preferably 1:1-1.5.

In the present invention, the mass ratio of the (R)-glycidol to the first organic solvent is preferably 19.6 g: 200-500 mL, more preferably 19.6 g: 320-450 mL.

In the present invention, the mixed solution in which the (R)-glycidol and the first acylating agent are dissolved in the first organic solvent preferably further includes a dehydrating agent, and the dehydrating agent preferably includes N,N-dicyclohexylcarbobis imine, triethylamine or 4-dimethylaminopyridine. In the present invention, the mass ratio of the (R)-glycidol to the dehydrating agent is preferably 19.6:0.32-55, more preferably 19.6:28-54.5. In the present invention, the solution to be reacted obtained by dissolving (R)-glycidol and the first acylating agent in the first organic solvent is preferably heated to the temperature required for the first acylation reaction, and then the dehydrating agent is added.

The present invention has no special requirements on the method of dissolving, as long as it can be completely dissolved.

In the present invention, the temperature of the first acylation reaction is preferably -15 to 50°C; the time of the first acylation reaction is preferably 2 to 8 hours. In the present invention, when the first acylation reagent is a carboxylic acid, the temperature of the first acylation reaction is preferably 45 to 50° C., and the time of the first acylation reaction is preferably 7 to 8 hours; When the acylation reagent is an acid anhydride, the temperature of the first acylation reaction is preferably 25-30°C, and the time of the first acylation reaction is preferably 4 to 5 hours; when the first acylation reagent is an acid chloride, the The temperature of the first acylation reaction is preferably -15 to -10°C, and the time of the first acylation reaction is preferably 2 to 3 hours. In the present invention, the first acylation reaction is preferably accompanied by stirring. In the present invention, the stirring is not particularly limited as long as the reaction can be sufficiently advanced.

In the present invention, the equation of the first acylation reaction is shown in formula 1:

In the present invention, after the first acylation reaction, it is preferable to further include: cooling the system after the first acylation reaction and filtering, and concentrating the filtrate obtained by filtration and then recrystallization to obtain (S)-glycidyl fatty acid ester .

In the present invention, the temperature of the system after cooling is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, more preferably 25-30°C. The present invention has no particular limitation on the cooling method, as long as the desired temperature can be achieved. The present invention has no special requirements for the filtration, and a conventional filtration method in the art can be used. In the present invention, the concentration is preferably concentration under reduced pressure. The present invention has no special requirements for the concentration under reduced pressure, as long as most of the solvent in the system can be removed. In the present invention, the recrystallization solvent preferably includes a mixture of dichloromethane and methanol, a mixture of toluene and isopropanol, a mixture of ethyl acetate and n-butanol, or a mixture of acetone and n-hexane. In the present invention, the mass ratio of the mixed solution of dichloromethane and methanol to dichloromethane and methanol is preferably 1:2.8˜3.2, more preferably 1:3. In the present invention, the mass ratio of toluene and isopropanol in the mixed solution of toluene and isopropanol is preferably 1:2.8-3.2, more preferably 1:3. In the present invention, the mass ratio of ethyl acetate and n-butanol in the mixed solution of ethyl acetate and n-butanol is preferably 1:2.8-3.2, more preferably 1:3. In the present invention, the mass ratio of acetone and n-hexane in the mixed solution of acetone and n-hexane is preferably 1:2.8-3.2, more preferably 1:3. In the present invention, the mass ratio of the crude product obtained after the concentration to the solvent for recrystallization is preferably 1:3.8 to 4.2, more preferably 1:4.

After the (S)-glycidyl fatty acid ester is obtained, the present invention mixes the (S)-glycidyl fatty acid ester, phosphorylcholine and the second organic solvent, and performs a ring-opening reaction to obtain the lysophosphatidylcholine . In the present invention, the second organic solvent preferably includes toluene, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, isopropanol, n-butanol, tert-butanol , one or more of ethylene glycol methyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide and sulfolane, more preferably ethylene glycol methyl ether, sulfolane or, N,N-dimethylformamide . In the present invention, when the second organic solvent includes two or more of the above-mentioned specific substances, the present invention does not specifically limit the proportion of the specific substances, and any proportion may be used.

In the present invention, the mass ratio of the (S)-glycidyl fatty acid ester to the volume ratio of the second organic solvent is preferably 32.8-91 g:400-450 mL, more preferably 32.8-90.5 g:400-420 mL. In the present invention, the molar ratio of the phosphorylcholine and (S)-glycidyl fatty acid ester is preferably 1:1-1.5, more preferably 1:1.2-1.4.

In the present invention, the ring-opening reaction is preferably carried out under catalyst conditions; the catalyst preferably includes one or more of transition metal oxides, sulfuric acid, nitric acid, hydrochloric acid, cation resin and solid super acid, more preferably Transition metal oxides, sulfuric acid or solid superacids. In the present invention, the transition metal oxide preferably includes acidic alumina. In the present invention, the solid superacid preferably includes zirconia-sulfuric acid solid superacid. In the present invention, when the catalyst includes two or more of the above-mentioned specific substances, the present invention does not specifically limit the ratio of the specific substances, and any ratio may be used.

In the present invention, the molar ratio of the phosphorylcholine to the catalyst is preferably 1:0.1-1, more preferably 1:0.2-0.8.

The present invention has no special requirements for the mixing as long as the mixing can be uniform. In the present invention, the temperature of the ring-opening reaction is preferably 60-150°C, more preferably 70-140°C; the time of the ring-opening reaction is preferably 12-48h, more preferably 15-40h.

In the present invention, the ring-opening reaction is preferably accompanied by stirring, and the present invention has no special requirements for the stirring, as long as the reaction can be sufficiently carried out.

In the present invention, the equation of the ring-opening reaction is shown in formula 2:

In the present invention, the ring-opening reaction preferably further includes: cooling the system after the ring-opening reaction, filtering, and concentrating the filtrate obtained by filtration and then recrystallization to obtain lysophosphatidylcholine.

In the present invention, the temperature of the system after cooling is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, more preferably 25-30°C. The present invention has no particular limitation on the cooling method, as long as the desired temperature can be achieved. The present invention has no special requirements for the filtration, and a conventional filtration method in the art can be used. In the present invention, the concentration is preferably concentration under reduced pressure. The present invention has no special requirements for the concentration under reduced pressure, as long as most of the solvent in the system can be removed. In the present invention, the solvent for recrystallization preferably includes a mixture of ethyl acetate and n-hexane, a mixture of chloroform and diethyl ether, or a mixture of acetonitrile and methyl tert-butyl ether, more preferably ethyl acetate and n-hexane A mixture of alkane or a mixture of chloroform and ether. In the present invention, when the solvent for recrystallization is a mixed solution of ethyl acetate and n-hexane, the mass ratio of the ethyl acetate and n-hexane is preferably 0.8-1.2:1 by mass, more preferably 1:1 ; The temperature of the recrystallization is preferably -1 to 1°C, more preferably 0°C. In the present invention, when the solvent for recrystallization is a mixed solution of chloroform and diethyl ether, the mass ratio of the chloroform and diethyl ether is preferably 2.8-3.2:5, more preferably 3:5; the recrystallization temperature Preferably it is 38-42 degreeC, More preferably, it is 40 degreeC. In the present invention, when the recrystallization solvent is a mixed solution of acetonitrile and methyl tert-butyl ether, the mass ratio of the acetonitrile and methyl tert-butyl ether is preferably 1.8-2.2:6, more preferably 2:6; the temperature of the recrystallization is preferably -42 to -38°C, more preferably -40°C. In the present invention, the mass ratio of the crude product obtained after the concentration to the solvent for recrystallization is preferably 1:7.8-8.2, more preferably 1:8. In the present invention, the number of times of the recrystallization is preferably 1 to 5 times, and more preferably 2 to 4 times.

After the lysophosphatidylcholine is obtained, the present invention dissolves the lysophosphatidylcholine and the second acylating agent in a third organic solvent, and performs a second acylation reaction to obtain the phosphatidylcholine. In the present invention, the second acylating reagent preferably includes carboxylic acid, acid chloride or acid anhydride, more preferably carboxylic acid or acid anhydride. In the present invention, the number of carbon atoms in the carboxylic acid, acid chloride and acid anhydride independently is preferably 8-27, more preferably 10-16. In the present invention, the carboxylic acid preferably has the structure shown in formula b-1; the acid chloride preferably has the structure shown in b-2; the acid anhydride preferably has the structure shown in formula b-3;

Among them, R ² is preferably a C7-C26 alkyl group or a substituted alkyl group, and more preferably a C7-C26 alkyl group. In the present invention, the carboxylic acid preferably includes fatty acid, n-octanoic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, oleic acid or arachidonic acid, more preferably arachidic acid, oleic acid, or arachidonic acid acid. In the present invention, the acid chloride preferably includes fatty acid chloride, myristoyl chloride, palmitoyl chloride or stearoyl chloride, more preferably myristoyl chloride or stearoyl chloride. In the present invention, the acid anhydride preferably includes fatty acid anhydride, lauric anhydride, stearic anhydride or oleic anhydride, more preferably lauric anhydride or oleic anhydride.

In the present invention, the acyl groups provided by the first acylation reagent and the second acylation reagent are preferably inconsistent, that is, R ¹ and R ² are different groups.

In the present invention, the third organic solvent preferably includes acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethylformamide One or more of ether, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane and toluene and xylene, more preferably toluene, sulfolane or dimethyl sulfoxide, more preferably toluene or dimethyl sulfoxide methyl sulfoxide.

In the present invention, the molar ratio of the lysophosphatidylcholine to the second acylating agent is preferably 1:1-1.8, more preferably 1:1.2-1.6.

In the present invention, the mass ratio of the blood phosphatidylcholine to the volume of the third organic solvent is preferably 115-150 g:500 mL, more preferably 120-145 g:500 mL.

In the present invention, the mixed solution obtained by dissolving the lysophosphatidylcholine and the second acylating agent in the third organic solvent preferably further includes a dehydrating agent, and the dehydrating agent preferably includes N,N-dicyclohexylcarbobis imine (DCC), triethylamine or 4-dimethylaminopyridine (DMAP). In the present invention, the mass ratio of the lysophosphatidylcholine to the dehydrating agent is preferably 115-150:0.32-55, more preferably 120-145:28-55. In the present invention, preferably, the solution to be reacted obtained by dissolving lysophosphatidylcholine and the second acylation reagent in the third organic solvent is heated to the temperature required for the second acylation reaction, and then the dehydrating agent is added.

The present invention has no special requirements on the method of dissolving, as long as it can be completely dissolved.

In the present invention, the temperature of the second acylation reaction is preferably 50 to 150° C.; the time of the acylation reaction is preferably 8 to 24 hours. In the present invention, when the second acylation reagent is a carboxylic acid, the temperature of the second acylation reaction is preferably 145-150°C, and the time of the second acylation reaction is preferably 22 to 24 hours; When the acylating reagent is an acid anhydride, the temperature of the second acylation reaction is preferably 100-110°C, and the time of the second acylation reaction is preferably 14-16 h; when the second acylation reagent is an acid chloride, the The temperature of the second acylation reaction is preferably 50˜60° C., and the time of the second acylation reaction is preferably 8˜10 h. In the present invention, the second acylation reaction is preferably accompanied by stirring. In the present invention, the stirring is not particularly limited as long as the reaction can be sufficiently advanced.

In the present invention, the equation of the second acylation reaction is shown in formula 3:

In the present invention, after the second acylation reaction, it preferably further comprises: cooling the system after the second acylation reaction, filtering, and concentrating the filtrate obtained by filtration and then recrystallization to obtain phosphatidylcholine.

In the present invention, the temperature of the system after cooling is preferably room temperature, and the temperature of the room temperature is preferably 20-35°C, more preferably 25-30°C. The present invention has no particular limitation on the cooling method, as long as the desired temperature can be achieved. The present invention has no special requirements for the filtration, and a conventional filtration method in the art can be used. In the present invention, the concentration is preferably concentration under reduced pressure. The present invention has no special requirements for the concentration under reduced pressure, as long as most of the solvent in the system can be removed. In the present invention, the solvent for recrystallization preferably includes a good solvent for phosphatidylcholine and a poor solvent for phosphatidylcholine. In the present invention, the good solvent for phosphatidylcholine preferably includes acetonitrile, ethyl acetate, dichloromethane, dichloroethane, toluene, xylene, chloroform, methanol, ethanol, n-butanol, isopropanol and tertiary One or more of butanols, more preferably toluene, methanol or acetonitrile. In the present invention, the mass ratio of the concentrated solution to the good solvent is preferably 2 to 4:1, more preferably 3:1. In the present invention, the poor solvent of the phosphatidylcholine preferably includes one or more of n-hexane, cyclohexane, acetone, methyl ethyl ketone, diethyl ether and methyl tert-butyl ether, more preferably n-hexane, butanone or methyl tert-butyl ether. In the present invention, the mass ratio of the concentrated solution to the poor solvent is preferably 4 to 6:1, more preferably 5:1. In an embodiment of the present invention, the recrystallization solvent is specifically a mixed solution of toluene and methyl ethyl ketone with a mass ratio of 3:5, a mixed solution of acetonitrile and methyl tert-butyl ether with a mass ratio of 2:6 or A mixture of methanol and n-hexane with a mass ratio of 1:1. In an embodiment of the present invention, the mass ratio of the concentrated solution to the solvent for recrystallization is specifically 1:8.

In the present invention, the temperature of the recrystallization is preferably -40 to 40°C, more preferably 0 to 20°C. In the present invention, the number of times of recrystallization is preferably 1 to 5 times, and more preferably 2 to 4 times.

In the present invention, the reactant with clear structure and single carbon chain length can ensure that the prepared phosphatidylcholine has a clear structure, and the asymmetrical structure can be obtained only by adjusting the types of the first acylation reagent and the second acylation reagent. of phosphatidylcholine.

In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below with reference to the examples, but they should not be construed as limiting the protection scope of the present invention.

Example 1

(R)-glycidol (19.6g, 0.264mol) and n-octanoic acid (68.5g, 0.475mol) were dissolved in 320mL 1,4-dioxane, the temperature was raised to 50°C, the dehydrating agent N,N-dicyclohexyl was added. Carbodiimide (DCC) (54.5g, 0.264mol) was added to the solution, the first acylation reaction was carried out (with stirring) for 8h, cooled to 25°C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product; using the mass ratio Be that the mixed solvent of toluene and isopropanol of 1:3 carries out recrystallization to the obtained crude product (the mass ratio of crude product and mixed solvent is 1:4) to obtain 49.6g (S)-glycidyl n-octanoate;

Phosphorylcholine (30.2 g, 0.164 mol), (S)-glycidyl n-octanoate (32.8 g, 0.164 mol) and 400 mL of ethylene glycol methyl ether were mixed, and the temperature was raised to 60 ° C to carry out a ring-opening reaction (with stirring). ) 12h, cooled to room temperature, filtered, collected the filtrate, concentrated under reduced pressure to obtain the crude product; under the condition that the temperature was 0 °C, the crude product was recrystallized by using a mixture of ethyl acetate and n-hexane with a mass ratio of 1:1 (the crude product and The mass ratio of the mixed solution was 1:8) 3 times to obtain 38.3 g of n-octanoyl lysophosphatidylcholine;

Dissolve n-octanoyl lysophosphatidylcholine (101.1 g, 0.264 mol) and n-octanoic anhydride (52.3 g, 0.370 mol) in toluene (500 mL), and add 4-dimethylaminopyridine ( DMAP, 0.32g, 2.64mmol) carried out the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, collected the filtrate, concentrated under reduced pressure to obtain the crude product, at a temperature of 0°C, with a mass ratio of 3: The crude product was recrystallized with the mixed solution of toluene and butanone of 5 (the mass ratio of the crude product and the mixed solution was 1:8) 3 times to obtain 116.9 g of di-n-octanoylphosphatidylcholine.

Example 2

(R)-glycidol (19.6g, 0.264mol) and lauric acid (95.1g, 0.475mol) were dissolved in 320mL 1,4-dioxane, the temperature was raised to 50°C, the dehydrating agent N,N-bicyclo Hexylcarbodiimide (DCC) (54.5g, 0.264mol) was added to the solution, the first acylation reaction was carried out (with stirring) for 8h, cooled to 25°C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product; Ratio is that the mixed solvent of toluene and isopropanol of 1:3 carries out recrystallization to the crude product obtained (the mass ratio of crude product and mixed solvent is 1:4) to obtain 63.5g (S)-glycidyl laurate;

Phosphorylcholine (30.2 g, 0.164 mol), (S)-glycidyl laurate (42.0 g, 0.164 mol), sulfuric acid (1.6 g, 16.4 mmol) and ethylene glycol methyl ether (400 mL) were mixed, and the temperature was raised to 60°C, carry out ring-opening reaction (with stirring) for 12h, cool to 25°C, filter, collect the filtrate, and concentrate under reduced pressure to obtain the crude product. The mixed solution of alkane carries out recrystallization to crude product (the mass ratio of crude product and mixed solution is 1:8) 3 times to obtain 46.8g lauroyl lysophosphatidylcholine;

Lauroyl lysophosphatidylcholine (115.9 g, 0.264 mol) and lauric anhydride (141.4 g, 0370 mol) were dissolved in toluene (500 mL), and the temperature was raised to 100 °C, and 4-dimethylaminopyridine (DMAP, 0.32g, 2.64mmol) for the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, the filtrate was collected, concentrated under reduced pressure to obtain the crude product, at a temperature of 0°C, with a mass ratio of 3:5 The crude product was recrystallized with a mixed solution of toluene and butanone (the mass ratio of the crude product and the mixed solution was 1:8) 3 times to obtain 142.6 g of dilauroylphosphatidylcholine.

Example 3

(R)-glycidol (19.6g, 0.264mol) and dichloromethane (320mL) were mixed and cooled to -15°C, triethylamine (28.1g, 0.278mol) was added to the mixture, myristoyl chloride ( 65.2g, 0.264mol) was added (with stirring) at a constant speed to the mixed solution of (R)-glycidol, dichloromethane and triethylamine through a constant pressure dropping funnel within 1 hour, continued the reaction (with stirring) for 1h, filtered, The filtrate was collected and concentrated under reduced pressure to obtain the crude product; the mixed solvent of ethyl acetate and n-butanol with a mass ratio of 1:3 was used to recrystallize the obtained crude product to obtain 68.2g (S)-glycidyl myristate;

Phosphorylcholine (30.2g, 0.164mol), (S)-glycidyl myristate (69.9g, 0.246mol), acid alumina (16.6g, 0.164mol) and sulfolane (420mL) were mixed and the temperature was raised to 150 ℃, carry out ring-opening reaction (with stirring) for 48h, cool to 25℃, filter, collect the filtrate, and concentrate under reduced pressure to obtain crude product. The crude product was recrystallized (the mass ratio of the crude product and the mixed solution was 1:8) once to obtain 50.5 g of myristoyl lysophosphatidylcholine;

Myristoyl lysophosphatidylcholine (123.3 g, 0.264 mol), myristic anhydride (162.3 g, 0.370 mol) and toluene (500 mL) were mixed, and the temperature was raised to 100°C, and 4-dimethylaminopyridine was added to the mixed solution (DMAP, 0.32g, 2.64mmol) to carry out the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, collected the filtrate, concentrated under reduced pressure to obtain the crude product, at a temperature of 0°C, with a mass ratio of 3 : 5 mixed solvent of toluene and butanone to recrystallize the crude product (the mass ratio of the crude product and the mixed solution is 1:8) 3 times to obtain 148.3 g of dimyristoyl phosphatidylcholine.

Example 4

(R)-glycidol (19.6g, 0.264mol) and palmitic acid (121.8g, 0.475mol) were dissolved in 320mL 1,4-dioxane, the temperature was raised to 50°C, the dehydrating agent N,N-bicyclo Hexylcarbodiimide (DCC) (54.5g, 0.264mol) was added to the solution, the first acylation reaction was carried out (with stirring) for 8h, cooled to 25°C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product; The mixed solvent of toluene and isopropanol with a ratio of 1:3 carries out recrystallization to the obtained crude product (the mass ratio of crude product and mixed solvent is 1:4) to obtain 73.3g (S)-glycidyl palmitate;

Phosphorylcholine (30.2g, 0.164mol), (S)-glycidyl palmitate (76.8g, 0.246mol), acid alumina (16.6g, 0.164mol) and sulfolane (420mL) were mixed and the temperature was raised to 150°C , carry out the ring-opening reaction (with stirring) for 48h, cool to 25°C, filter, collect the filtrate, and concentrate under reduced pressure to obtain the crude product. The crude product was recrystallized (the mass ratio of the crude product and the mixed solution was 1:8) once to obtain 56.8 g of palmitoyl lysophosphatidylcholine;

Palmitoyl lysophosphatidylcholine (123.3 g, 0.264 mol), palmitic anhydride (183.1 g, 0.370 mol) and toluene (500 mL) were mixed, and the temperature was raised to 100°C, and 4-dimethylaminopyridine (DMAP) was added to the mixed solution. , 0.32g, 2.64mmol) for the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, the filtrate was collected, concentrated under reduced pressure to obtain the crude product, at a temperature of 40°C, the mass ratio was 3:5 The crude product was recrystallized with a mixed solvent of toluene and butanone (the mass ratio of the crude product and the mixed solution was 1:8) once to obtain 164.5 g of dipalmitoyl phosphatidylcholine.

Example 5

(R)-glycidol (19.6g, 0.264mol) and triethylamine (28.1g, 0.278mol) were dissolved in 320mL of dichloromethane, cooled to -15°C, stearoyl chloride (80.0g, 0.264mol) was dissolved for 1h It was added dropwise at a uniform speed, and the reaction was incubated for 1 h, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product; the mixed solvent of methanol and dichloromethane with a mass ratio of 1:3 was used to obtain the crude product (the mass ratio of the crude product and the mixed solvent was 1:4) carry out recrystallization to obtain 82.5g (S)-glycidyl stearate;

Phosphorylcholine (30.2g, 0.164mol), (S)-glycidyl stearate (83.6g, 0.246mol), acid alumina (16.6g, 0.164mol) and sulfolane (420mL) were mixed and the temperature was raised to 150 ℃, carry out the ring-opening reaction (with stirring) for 48h, cool to 25 ℃, filter, collect the filtrate, and concentrate under reduced pressure to obtain the crude product. Liquid carries out recrystallization to crude product (the mass ratio of crude product and mixed solution is 1:8) 1 time, obtains 59.2g stearoyl lysophosphatidylcholine;

Stearoyl lysophosphatidylcholine (138.1 g, 0.264 mol), stearic anhydride (183.1 g, 0.370 mol) and toluene (500 mL) were mixed, and the temperature was raised to 100°C, and 4-dimethylaminopyridine was added to the mixed solution (DMAP, 0.32g, 2.64mmol) to carry out the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, the filtrate was collected, concentrated under reduced pressure to obtain the crude product, at a temperature of 40°C, with a mass ratio of 3 : 5 mixed solvent of toluene and butanone to recrystallize the crude product (the mass ratio of crude product and mixed solution is 1:8) once to obtain 183.3 g of distearoyl phosphatidyl choline.

Example 6

(R)-glycidol (19.6g, 0.264mol) and triethylamine (28.1g, 0.278mol) were dissolved in 320mL of dichloromethane, cooled to -15°C, arachidonic acid chloride (87.4g, 0.264mol) was dissolved within 1h Uniform dropwise addition, then incubated for 1h, filtered, collected the filtrate, concentrated under reduced pressure to obtain the crude product; Utilizing the mixed solvent of methanol and dichloromethane with a mass ratio of 1:3 to the obtained crude product (the mass ratio of the crude product and the mixed solvent was 1 : 4) carry out recrystallization, obtain 92.3g (S)-glycidyl arachidonic acid ester;

Phosphorylcholine (30.2g, 0.164mol), (S)-glycidyl arachidonate (90.5g, 0.246mol), acid alumina (16.6g, 0.164mol) and sulfolane (420mL) were mixed and heated to 150°C , carried out the ring-opening reaction (with stirring) for 48h, cooled to 25°C, filtered, collected the filtrate, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized (the mass ratio of the crude product and the mixed solution was 1:8) 1 time to obtain 63.3 g of arachidyl lysophosphatidylcholine;

Arachidyl lysophosphatidylcholine (145.5g, 0.264mol), arachidonic acid (148.4g, 0.475mol) and sulfolane (500mL) were mixed, and the temperature was raised to 150°C, and N,N-dicyclohexylcarbon was added to the mixed solution Diimine (DCC, 54.5 g, 0.264 mmol) was subjected to the second acylation reaction (with stirring) for 24 h, cooled to 25 °C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized with a mixed solvent of toluene and methyl ethyl ketone with a mass ratio of 3:5 (the mass ratio of the crude product and the mixed solution was 1:8) once to obtain 200.8 g of diarachidonylphosphatidylcholine.

Example 7

(R)-glycidol (19.6 g, 0.264 mol) and oleic anhydride (202.2 g, 0.370 mol) were dissolved in toluene (450 mL), the temperature was raised to 30 °C, and 4-dimethylaminopyridine (DMAP, 4-dimethylaminopyridine) was added to the solution. 0.32g, 2.64mmol) carried out the first acylation reaction (with stirring) for 5h, cooled to 25°C, filtered, collected the filtrate, concentrated under reduced pressure to obtain (S)-glycidyl oleate crude product, the mass ratio was 1:3 The crude product was recrystallized with a mixed solvent of acetone and n-hexane (-5°C) to obtain 77.7g (S)-glycidyl oleate;

Phosphocholine (30.2g, 0.164mol), (S)-glycidyl oleate (66.6g, 0.197mol), zirconia-sulfuric acid solid superacid (10.1g, 0.082mol) and N,N-dimethyl Alkylformamide (420 mL) was mixed, heated to 100 °C, and subjected to ring-opening reaction (with stirring) for 30 h, cooled to 25 °C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product. The mixed solution of acetonitrile and methyl tertiary butyl ether having a ratio of 2:6 recrystallizes the crude product (the mass ratio of the crude product and the mixed solution is 1:8) 5 times to obtain 47g of oleoyl lysophosphatidylcholine;

Oleoyl lysophosphatidylcholine (137.5 g, 0.264 mol), oleic acid (134.2 g, 0.475 mol) and toluene (500 mL) were mixed, and the temperature was raised to 150°C, and 4-dimethylaminopyridine (DMAP) was added to the mixed solution. , 0.32g, 2.64mmol) carried out the second acylation reaction (with stirring) for 14h, cooled to 25°C, filtered, collected the filtrate, concentrated under reduced pressure to obtain the crude product, at a temperature of -40°C, the mass ratio was 2: The crude product was recrystallized with a mixed solvent of 6 of acetonitrile and methyl tert-butyl ether (the mass ratio of the crude product and the mixed solution was 1:8) 4 times to obtain 149.2 g of dioleoylphosphatidylcholine.

Example 8

(R)-glycidol (19.6g, 0.264mol) and arachidonic anhydride (218.3g, 0.370mol) were dissolved in 450mL of toluene, the temperature was raised to 30°C, and then 4-dimethylaminopyridine (DMAP) (0.32g , 2.64mmol) added reaction system, insulation reaction 5h, filtered, collected filtrate, concentrated under reduced pressure to obtain crude product; Utilize the mixed solvent of acetone and n-hexane of 1:3 to obtain crude product (the mass ratio of crude product and mixed solvent) Be 1:4) carry out recrystallization, obtain 76.2g (S)-glycidyl arachidonic acid ester;

Phosphorylcholine (30.2g, 0.164mol), (S)-glycidyl arachidonate (70.9g, 0.197mol), zirconia-sulfuric acid solid superacid (10.1g, 0.082mol) and N,N- After mixing with dimethylformamide (400 mL), the temperature was raised to 100 °C, the ring-opening reaction was carried out (with stirring) for 30 h, cooled to 25 °C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized (the mass ratio of the crude product and the mixed solution was 1:8) 5 times with the mixed solution of acetonitrile and methyl tertiary butyl ether having a mass ratio of 2:6 to obtain 38.3 g of arachidyl lysophosphatidyl choline;

Arachidoyl lysophosphatidylcholine (143.4g, 0.264mol), arachidonic acid (144.7g, 0.475mol) and sulfolane (500mL) were mixed, and the temperature was raised to 150°C, and N,N- Dicyclohexylcarbodiimide (DCC, 54.5g, 0.264mmol) was subjected to the second acylation reaction (with stirring) for 24h, cooled to 25°C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product at -40°C Under the condition, the mixed solvent of acetonitrile and methyl tertiary butyl ether with a mass ratio of 2:6 is used to recrystallize the crude product (the mass ratio of the crude product and the mixed solution is 1:8) 5 times to obtain 142.4g diarachidonic acid. Phosphatidylcholine.

Example 9

Prepare stearoyl lysophosphatidylcholine according to the method of embodiment 5;

Stearoyl lysophosphatidylcholine (138.1 g, 0.264 mol), oleic acid (134.2 g, 0.475 mol) and sulfolane (500 mL) were mixed, and the temperature was raised to 150 °C, and the dehydrating agent N,N-diol was added to the mixture. Cyclohexylcarbodiimide (DCC, 54.5g, 0.264mol) was subjected to the second acylation reaction (with stirring) for 24h, cooled to 25°C, filtered, the filtrate was collected, and concentrated under reduced pressure to obtain the crude product, at a temperature of -40°C Next, the mixed solvent of acetonitrile and methyl tertiary butyl ether with a mass ratio of 2:6 carries out recrystallization to the crude product (the mass ratio of the crude product and the mixed solution is 1:8) 3 times to obtain 153.7g 1-stearoyl -2-Oleoylphosphatidylcholine.

Example 10

Prepare stearoyl lysophosphatidylcholine according to the method of embodiment 5;

Stearoyl lysophosphatidylcholine (138.1 g, 0.264 mol) and dimethyl sulfoxide (500 mL) were mixed, and the temperature was raised to 50°C. Triethylamine (28.1 g, 0.278 mol) was added to the mixture, and the palm Acyl chloride (72.5 g, 0.264 mol) was added to the mixture of stearoyl lysophosphatidylcholine, dimethyl sulfoxide (500 mL) and triethylamine through a constant pressure dropping funnel within 7 hours, and kept stirring for 1 hour. to 25°C, filter, collect the filtrate, and concentrate under reduced pressure to obtain the crude product. Under the condition that the temperature is 40°C, the crude product is recrystallized with a mixed solvent of methanol and n-hexane with a mass ratio of 1:1 (the quality of the crude product and the mixed solution). The ratio is 1:8) 1 time to obtain 186.8 g of 1-stearoyl-2-palmitoylphosphatidylcholine.

Example 11

Prepare palmitoyl lysophosphatidylcholine according to the method of embodiment 4;

The palmitoyl lysophosphatidylcholine (130.7g, 0.264mol) and dimethyl sulfoxide (500mL) were mixed, and the temperature was raised to 50°C, and triethylamine (28.1g, 0.278mol) was added to the mixture to disperse stearoyl chloride. (82.5g, 0.264mol) was added to the mixed solution of palmitoyl lysophosphatidylcholine, dimethyl sulfoxide and triethylamine through a constant pressure dropping funnel within 7 hours, kept stirring for 1 hour, cooled to 25°C, and filtered. , the filtrate was collected, concentrated under reduced pressure to obtain the crude product, and at a temperature of 40 ° C, the crude product was recrystallized with the mixed solvent of methanol and n-hexane with a mass ratio of 1:1 (the mass ratio of the crude product and the mixed solution was 1:8 ) once to obtain 186.8 g of 1-palmitoyl-2-stearoylphosphatidylcholine.

The yields of (S)-glycidyl fatty acid ester, lysophosphatidylcholine and phosphatidylcholine in the calculated examples 1 to 11 are listed in Table 1; The purities of choline and phosphatidylcholine are listed in Table 1.

The yield and purity of intermediate products and final products in Table 1 Examples 1-11

The lauroyl lysophosphatidylcholine prepared in Example 2 was subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 1; the lauroyl lysophosphatidylcholine prepared in Example 2 was subjected to liquid chromatography detection to obtain The liquid chromatogram is shown in Figure 2; the dilauroyl phosphatidylcholine prepared in Example 2 is subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 3; the dilauroyl phospholipid prepared in Example 2 is Acylcholine was detected by liquid chromatography, and the liquid chromatogram was obtained as shown in Figure 4.

The myristoyl lysophosphatidyl choline prepared in Example 3 was subjected to nuclear magnetic detection to obtain the ¹ H NMR spectrum of myristoyl lysophosphatidyl choline as shown in Figure 5; Phosphatidylcholine was detected by liquid chromatography, and the liquid chromatogram was shown in Figure 6; the dimyristoyl phosphatidylcholine prepared in Example 3 was subjected to nuclear magnetic detection, and the ¹ H NMR spectrum was shown in Figure 7 ; The dimyristoyl phosphatidyl choline prepared in Example 3 was detected by liquid chromatography, and the liquid chromatogram was obtained as shown in Figure 8 .

The palmitoyl lysophosphatidylcholine prepared in Example 4 was subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 9; the palmitoyl lysophosphatidylcholine prepared in Example 4 was subjected to liquid chromatography detection to obtain The liquid chromatogram is shown in Figure 10; the dipalmitoyl phosphatidylcholine prepared in Example 4 was subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 11; the dipalmitoyl phospholipid prepared in Example 4 was Acylcholine was detected by liquid chromatography, and the liquid chromatogram was obtained as shown in Figure 12.

The stearoyl lysophosphatidylcholine prepared in Example 5 was subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 13; the stearoyl lysophosphatidylcholine prepared in Example 5 was subjected to liquid chromatography detection , the liquid chromatogram is shown in Figure 14; the distearoyl phosphatidylcholine prepared in Example 5 is subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 15; Stearoyl phosphatidyl choline was detected by liquid chromatography, and the liquid chromatogram was obtained as shown in Figure 16.

The dioleoylphosphatidylcholine prepared in Example 7 was subjected to nuclear magnetic detection to obtain a ¹ H NMR spectrum as shown in Figure 17; the dioleoylphosphatidylcholine prepared in Example 7 was subjected to liquid chromatography detection to obtain The liquid chromatogram is shown in FIG. 18 .

The ¹ -stearoyl-2-palmitoylphosphatidylcholine prepared in Palmitoylphosphatidylcholine was detected by liquid chromatography, and the liquid chromatogram was obtained as shown in Figure 20.

The present invention assigns hydrogen in different chemical environments according to the ¹ H NMR spectrum, so as to clarify the product structure, confirming that the intermediate product prepared in the example is lysophosphatidyl choline, and the intermediate product is phosphatidyl choline, as given in the present invention At the same time, according to the difference in the retention time of different substances in the high performance liquid chromatogram, the structure and purity can also be confirmed by comparing with the standard sample.

Although the above embodiment has made a detailed description of the present invention, it is only a part of the embodiments of the present invention, rather than all the embodiments. People can also obtain other embodiments according to the present embodiment without creativity. These embodiments All belong to the protection scope of the present invention.

Claims (10)

1. a preparation method of phosphatidylcholine, comprises the following steps: Dissolving (R)-glycidol and the first acylating agent in the first organic solvent, and carrying out the first acylation reaction to obtain (S)-glycidyl fatty acid ester; Mixing the (S)-glycidyl fatty acid ester, phosphorylcholine and the second organic solvent, and carrying out a ring-opening reaction to obtain the lysophosphatidylcholine; The lysophosphatidylcholine and the second acylation reagent are dissolved in the third organic solvent, and the second acylation reaction is performed to obtain the phosphatidylcholine. 2 . The preparation method according to claim 1 , wherein the first acylating reagent and the second acylating reagent independently comprise carboxylic acid, acid chloride or acid anhydride. 3 . 3 . The preparation method according to claim 2 , wherein the number of carbon atoms in the carboxylic acid, acid chloride and acid anhydride is independently 8-27. 4 . 4. preparation method according to claim 3 is characterized in that, described carboxylic acid comprises n-octanoic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, oleic acid or arachidonic acid; The acid chloride includes fatty acid chloride, myristoyl chloride, palmitoyl chloride or stearoyl chloride; The acid anhydride includes fatty acid anhydride, lauric anhydride, stearic anhydride or oleic anhydride. 5. The preparation method according to any one of claims 1 to 4, wherein the molar ratio of the (R)-glycidol to the first acylating reagent is 1:1 to 1.8; The temperature of the first acylation reaction is -15˜50° C.; the time of the first acylation reaction is 2˜8 h. 6. The preparation method according to any one of claims 1 to 4, wherein the molar ratio of the lysophosphatidylcholine to the second acylating reagent is 1:1 to 1.8; The temperature of the second acylation reaction is 50˜150° C.; the time of the second acylation reaction is 8˜24 h. 7 . The preparation method according to claim 1 , wherein the molar ratio of the phosphorylcholine to (S)-glycidyl fatty acid ester is 1:1 to 1.5. 8 . 8. preparation method according to claim 1, is characterized in that, described ring-opening reaction is carried out under catalyst condition; The molar ratio of the phosphorylcholine and the catalyst is 1:0.1-1. 9 . The preparation method according to claim 8 , wherein the catalyst comprises one or more of transition metal oxides, sulfuric acid, nitric acid, hydrochloric acid, cation resin and solid superacid. 10 . 10 . The preparation method according to claim 4 , wherein the temperature of the ring-opening reaction is 60-150° C.; the time of the ring-opening reaction is 12-48 h. 11 .

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