JPS61207396A - Production of phosphatidylcholine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug, etc., industrially advantageously without using a heavy metal, by reacting glycerophosphorylcholine adsorbed on or impregnated into a carrier with an activated fatty acid in the presence of a catalyst in a solvent. CONSTITUTION:Glycerophosphorylcholine adsorbed on or impregnated into a carrier (e.g., silica gel, etc.) is reacted with an activated fatty acid (preferably 8-24C fatty acid anhydride, chloride, etc., such as palmitic anhydride, etc.) in the presence of a catalyst (e.g., dimethylaminopyridine in the case of acid anhydride, and pyrrolidinopyridine, etc. in the case of acid chloride, etc.) in a solvent (preferably dichloromethane containing dimethyl sulfoxide, etc.), to give the aimed compound. The fatty acid anhydride may be formed by feeding simultaneously the fatty acid and 1-twice molar amounts of a carbodiimide condensation agent and a starting raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a new method for producing phosphatidylcholine without using heavy metals.

[Conventional technology]

Phospholipids exist as components of biological membranes of cells, and in biological membranes, they form a bilayer membrane with a bimolecular structure, and together with proteins, cholesterol, etc., they are essential for biological phenomena such as selective transport of substances. It performs functions that cannot be performed. There are mainly phospholipids such as phosphatidylcholine (hereinafter referred to as PC), phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin in living organisms. Among these, PC is generally called lecithin and is the most abundant in living organisms. There are many of them, and their importance is recognized. A common feature of these phospholipids is that they have a parent group and a hydrophobic group within their molecules, which allows them to form vesicles called liposomes, which are characteristic of phospholipids, or to form Langmuir-like molecules on a substrate.・
Prodgett's method allows the creation of thin films with oriented molecules.

Natural phospholipids have already been used industrially as natural emulsifiers.
While it is used in the food and cosmetics industries, it is also being developed into medicine that takes advantage of its physiologically active effects.

Recently, it has been known that phospholipids form closed endoplasmic reticulum called liposomes, which have a bilayer membrane and have a bimolecular structure in water, and various uses for this are being considered. For example, medicine
In the pharmaceutical field, it is being considered for use in drug carriers, artificial blood, etc., and in the engineering field, it is being considered for use in artificial cells. Recently, thin films made from phospholipids are being applied to electronics, and the development of insulating films is being considered.

However, natural phospholipids are currently used for both purposes, but because phospholipids are mixtures, reproducibility is poor and their strength is insufficient, making it difficult to apply the original functions of phospholipids industrially. not present. In order to be applied to these uses, there is a need for phospholipids that have a structure and strength suitable for the purpose, and various attempts have been made for this purpose. For example, in order to use phospholipids as liposomes for drug carriers, they need to be relatively unaffected by degrading enzymes in the body and to be degraded after they have fulfilled their functions. For this purpose, polymerizable phospholipids are used as part of the liposome to create polymerized liposomes.

Attempts have been made to use phospholipids with ether bonds that are less susceptible to decomposition by enzymes. Furthermore, when considering the use as a thin film, polymerizable phospholipids are said to be preferable in order to increase the strength of the film.

Total synthesis method and semi-synthesis method have been known as methods for synthesizing PC (Baer et al., JACS 61(4), 7).
61 (1939), J. Biol, Chew.
230.447 (1958), JACS72, 942
(1950)), the total synthesis method requires many steps and is difficult to industrialize. The semi-synthetic method is a method of synthesizing PC from glycerophosphorylcholine (hereinafter referred to as GPC) and active fatty acids, and a heavy metal salt such as a cadmium salt is used as GPC. As activated fatty acids, (1) a method of converting fatty acids into acid chlorides and using them (Can, J., Bioc.
ham, Physiol, 37.953 (1959
)), (2) Method of using fatty acids as imidazole salts (JP-A-51-91213. Hermetter et al., C.
Hew.

Phys, Lipids 1981.28.111)
, and (3) a method using fatty acids as acid anhydrides (R
Egen et al., JACS (1982), 104.79
1) is known.

Among these methods, when acid chloride is used as a raw material, there is a strong possibility that double bonds will be chlorinated when unsaturated fatty acids are converted into acid chloride with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, etc. Although it is very difficult to handle because it is sensitive to water, it is an inexpensive and effective method for processing saturated fatty acids. Methods using imidazole salts as raw materials are often inconvenient, such as the imidazolization reagent being expensive and the use of metallic sodium. Compared to these methods, the method using acid anhydrides as raw materials is an effective method with milder synthesis and fewer by-products.

The method for synthesizing the acid anhydride used in this method is as follows:
A method for reacting acetic anhydride with a fatty acid (Wallace et al., JACS, 63.699 (1941)), a method for reacting an acid chloride and a fatty acid (Youngs et al., JA
Although methods such as OC5, 35° 416 (1958) have been known, these methods are quite radical and are not preferred for fatty acids having unsaturated bonds.

A mild acid anhydride conversion method uses N,N'-dicyclohexylcarbodiimide (Ringsdor
f et al., JACS, 1984. 1627) is known, and this method is mild and preferred for converting fatty acids with unsaturated bonds into acid anhydrides.

The conventional PC manufacturing method using this method is N, N'
- Dicyclohexylcarbodiimide (hereinafter referred to as DCC) is reacted with 1/2 molar equivalent of fatty acid in dry chloroform to generate fatty acid anhydride, and the precipitate is filtered and purified using a silica gel column or the like. , to obtain a purified fatty acid anhydride by drying, or to obtain a purified fatty acid anhydride as it is unpurified, with a cadmium chloride salt of GPC, etc., and dimethylaminopyridine (hereinafter referred to as DMAP) or pyrrolidinopyridine (hereinafter referred to as PPY), etc. This is a method of obtaining PC by a reaction using a catalyst, and the reaction is shown in the following reaction formula (1).

(In the formula, RCO- represents an acyl group.) The method using acid chloride is a method of obtaining PC by reacting acid chloride with cadmium chloride salt of GPC, etc., and the reaction is as follows: (In the formula, RCO- represents an acyl group.) [Problems to be Solved by the Invention] However, in these conventional methods.

One raw material, GPC, is extremely hygroscopic and has physical properties that make it highly viscous or easily form blocks at room temperature, making it difficult to handle.Moreover, the quaternary ammonium group of GPC is a secondary 011 ester. It is used as a heavy metal salt such as a cadmium chloride salt, as shown in Reaction Formula 1 (I) and (II), in order to facilitate handling and eliminate the influence of quaternary ammonium groups. It's here.

Another advantage of cadmium chloride salt is that crude G
When converting PC into purified GPC, purification could be achieved by recrystallizing it into cadmium chloride salt. However, this purification method has a low yield, so if GPC is synthesized from a raw material with high PC purity such as egg yolk lecithin, it will not be of any particular advantage industrially.

Currently, the harm caused by heavy metals to the human body is a serious problem, and cadmium is said to be the cause of Itai-tai disease, so it is not desirable to use heavy metals such as cadmium chloride. Also GPC
When PC is synthesized using cadmium chloride salt, GPC
1) is industrially difficult because it requires a cadmium chloride salt synthesis step and a cadmium salt removal step. There are many problems, such as the large amount of cost required for its disposal.

This invention is intended to solve the above-mentioned problems. By reacting GPC adsorbed or impregnated on a carrier with activated fatty acids, a simple process and process can be achieved without using cadmium chloride. The purpose of this invention is to propose a method for producing PC that can produce PC with high yield using an apparatus.

[Means for solving problems]

This invention is a method for producing phosphatidylcholine, which comprises mixing glycerophosphorylcholine adsorbed or impregnated onto a carrier and activated fatty acid in a solvent in the presence of a catalyst, and reacting the mixture.

Supports include silica gel, activated carbon, and zeolite.

Glass, 1m pottery, celite, activated clay, rock.

Alternatively, inorganic and organic substances capable of adsorbing or impregnating GPC, such as resin, can be used.

GPC, which is the raw material of the present invention, serves as the skeleton of synthesized PC, and can be obtained mainly by hydrolyzing or alcoholizing natural lecithin from soybean, egg yolk, etc. after separating and purifying it or as it is. Natural lecithin is separated using a silica gel column, activated alumina column, etc., and eluted with a chloroform/methanol mixed solvent. GPC can be obtained from purified or crude lecithin by alcoholysis with a quaternary alkyl ammonium hydroxide such as tetrabutylammonium hydroxide or an alkali metal, but it is possible to obtain GPC from purified or crude lecithin by gentle hydrolysis with a low concentration of alkali, etc. The GPC thus obtained is adsorbed or impregnated onto a carrier made of an inorganic or organic substance such as silica gel, activated carbon, zeolite, glass, pottery, porcelain, celite, activated clay, rock, or resin, and used for the reaction. In the method of adsorption or impregnation, GPC is dissolved in a suitable solvent such as methanol, brought into contact with a carrier, and the solvent is removed using an evaporator or the like, followed by adsorption or impregnation. G to adsorb or impregnate the carrier
The amount of PC is about 5 to 50% by weight.

As the fatty acid which is the next raw material of the present invention, natural or synthetic saturated or unsaturated fatty acids can be used, especially those having 8 carbon atoms.
~24 are preferred. Such fatty acids include naturally occurring fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, and linoleic acid, as well as synthetic fatty acids that have polymerizable groups or phenyl groups in their molecules.
These can be used alone or in any combination depending on the purpose. Polymerizable PC can be produced by using a fatty acid having a polymerizable group.

These fatty acids are reacted as activated fatty acids with GPC adsorbed or impregnated onto a carrier. Activated fatty acids include those activated to react with GPC, such as anhydrides, chlorides, or imidazolates of fatty acids.

In order to convert the fatty acid into an activated fatty acid, in the case of an acid anhydride, DCC, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, N,N'-diisopropylcarbodiimide, 1-cyclohexyl-3 It is preferable to convert the fatty acid into an acid anhydride using a carbodiimide condensing agent such as -(4-diethylaminocyclohexyl)carbodiimide and 1-ethyl-3-(diethylaminopropyl)carbodiimide. In addition, in the case of a saturated acid, an acid anhydride can be obtained by reacting it with acetic anhydride or its acid chloride.

Thionyl chloride for fatty acid chlorides.

It is obtained by reacting phosphorus trichloride, phosphorus pentachloride, etc. with fatty acids. Fatty acid imidazolates convert fatty acids into N
, N'-carbonyldiimidazole.

The catalyst used in the present invention is a catalyst for producing PC by reacting GPC with an activated fatty acid, and is preferably a mild catalyst that does not cause isomerization of PC.In the case of fatty acid anhydrides, DMAP, PPY, In the case of a chlorinated fatty acid, pyridine is preferred, and in the case of an imidazolized fatty acid, an imidazole alkali metal salt is preferred.

The solvent used in the reaction may be any solvent as long as it can disperse or dissolve each of the above components, such as dichloromethane, chloroform, carbon tetrachloride, and benzene.

Toluene, hexane, etc. can be used, but when dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, sulfolane, tetramethylurea, etc. are appropriately added to these, the solubility of GPC increases. These solvents preferred for the reaction are preferably used dry.

The method for producing PC is to react GPC adsorbed or impregnated on a carrier with a fatty acid anhydride, a fatty acid chloride, or a fatty acid imidazolate in the presence of a catalyst in a dry solvent such as dichloromethane. PC is produced by a reaction similar to II).

When using a fatty acid anhydride, the reaction can be carried out by the following method. That is, GPC1 fatty acid, which is adsorbed or impregnated onto a carrier in a dry solvent such as dichloromethane, using a carbodiimide condensing agent such as DCC in an amount equal to or more than the fatty acid;
A carbodiimide condensing agent and a catalyst are simultaneously charged and reacted. A condensing agent such as DCC may be added at any time during the reaction. PC is produced by carrying out the reaction at room temperature to 60° C. with stirring for 6 to 72 hours. The reaction at this time is shown by the following reaction formula [■].

r=−=−−−″−−−−−−−−−−−−−−−−
-1-m↓ DCC+ RCO○H-1→ This reaction occurs when a condensing agent such as DCC is present in the reaction system.
It utilizes the fact that fatty acids do not react with catalysts such as DMAP, but react with condensing agents to form acid anhydrides, [■]
In the formula, fatty acids are converted into acid anhydrides by DCC, and then converted into GP
PC is produced by the reaction with C, and the free fatty acid produced as a by-product is again converted into an acid anhydride by DCC and used for the reaction.

In this way, the fatty acids liberated by the reaction are always reacted with an excess of condensing agent to form acid anhydrides, and when this is reacted with GPC, the fatty acids are recycled into acid anhydrides, resulting in 9 reactions. The amount of fatty acids required for this process can be reduced, and the expensive catalyst does not produce free fatty acids and salts, making it effective even in small amounts.

The required amount of the condensing agent may be at least equimolar to the fatty acid, and even if added in large excess, the yield of PC will not be lowered, but an amount up to twice the number of moles of the fatty acid is suitable. The condensing agent may be added at appropriate times during the course of the reaction, or may be added in the required amount in advance at the start of the reaction.

After the reaction is completed, filtration, concentration, and purification are performed to obtain purified PC.

By selecting the fatty acid as the raw material, PC can be manufactured with various structures and strengths depending on the application.

The above PC manufacturing method does not use heavy metal salts such as cadmium chloride, so there is no need to worry about heavy metal contamination.
The produced PC can be used in medicines and foods, waste liquid treatment is simplified, the reaction process is shortened, and the yield is the same as the conventional cadmium salt method, producing PC at a high yield. be able to.

〔Effect of the invention〕

According to the present invention, Gpc adsorbed or impregnated on a carrier and activated fatty acids are mixed and reacted in the presence of a catalyst, so there is no need to use heavy metal salts such as cadmium salts, and the process is simple and easy. The device allows high yield PCt! :
can be manufactured easily, and waste liquid treatment becomes easy.

〔Example〕

The present invention will be specifically described below based on Reference Examples and Examples.

Reference Example-1 100 g of commercially available egg yolk lecithin was dissolved in 800 mρ of benzene, and 100 g of a 10% methanol solution of tetrabutylammonium hydroxide was added while stirring. Stirring was continued for 30 minutes after precipitation started, and then left to stand for 30 minutes. The crude GPC precipitated at the bottom was collected by decantation, and the crude GPC was poured into acetone 1i, which had been washed with benzene and cooled to -20°C.

A precipitate was obtained. Repeat the acetone reprecipitation in the same manner.

Crude GPC containing no impurities such as esters was recovered. This crude GPC was dissolved in methanol, and insoluble matter was removed by centrifugation. Evaporate the supernatant, 33. coarse G
The obtained PC was then dissolved again in 167 g of methanol,
A crude GPC methanol solution was obtained.

Reference Example-2 50 g of commercially available egg yolk lecithin was separated using a 1.5 Ω silica gel packed in a glass column with a diameter of 8 G.

Elution solvent: chloroform/methanol/water = 65/2
5/4 was used. The obtained PC31g 300tsQ
ノ/<:/ 31 g of a 10% methanol solution of tetrabutylammonium hydroxide was added while stirring. Then, 8.9 g of G was treated in the same manner as in Reference Example-1.
I got a PC. It was dissolved again in 50 g of methanol to obtain a GPC methanol solution.

Reference example-3 20 g (0,078 mol) of palmitic acid and DCC8
,0 g (0.04 mol) in dry chloroform at 5°C.
The reaction was allowed to proceed for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated to obtain crude palmitic anhydride. This crude palmitic anhydride was separated on a silica gel column using chloroform as an eluent to obtain 13.6 g (0,028 mol) of pure palmitic anhydride.

In the same manner, 14.6 g of pure oleic anhydride (0,0
27 mol) was obtained. (Reaction formula - [■]).

CC Dicyclohexylurea Example-1 40 g of the crude GPC methanol solution obtained in Reference Example-1 was added to 40 g of silica gel for column chromatography, and while methanol was removed in an evaporator, the crude GPC was adsorbed on the silica gel. Next, benzene was added and azeotropic dehydration was performed under reduced pressure to completely remove water and methanol. This rough G
Take 10 g of PC-adsorbed silica gel and add 11 g of palmitic acid anhydride (0,0223-1-/L) obtained in Reference Example-3.
z) and 2.0 g (0,0164 mol) of D M A P in 100 g of dichloromethane at room temperature for 48 hours. After the reaction, the anti-Is mixture was evaporated under reduced pressure and Soxhlet extracted with methanol for 24 hours. Next, the extract was treated with ion exchange resin Amberlite 200.
Pass it through a column of C (Rohm & Haas Inc. IN) and D
MAP was excluded. The effluent was concentrated and passed through a silica gel column using chloroform/methanol/water as eluent = 65/
Phosphatidylcholine cybalmitate (DPPC) 148 by purification using 25/4
I got g.

Example 2 Using 10 g of the crude GPC-adsorbed silica gel obtained in Example 1, a reaction was carried out in a mixed solvent of 70 g of dichloromethane and 30 g of dimethyl sulfoxide in the same manner as in Example 1. The reaction mixture was evaporated under reduced pressure and Soxhlet extracted with methanol for 24 hours. The extract was then passed through an Amberlite 200C column to remove DMAP.

The effluent was concentrated and poured into acetone 200tm Q at -20°C to obtain a precipitate. Purified in the same manner as in Example-1,
93 g of DPPCl was obtained.

Example 3 10 g of the GPC methanol solution obtained in Reference Example 2 was added to finely crushed ceramic zeolite Log, and GPC was impregnated while removing methanol in an evaporator. Next, benzene was added and azeotropic dehydration was performed under reduced pressure to completely remove water and methanol. This GPC-impregnated zeolite and Reference Example-3
11.6 g of palmitic anhydride (0,023
5 mol) and DMAP 2.2 g (0,0176 mol)
were reacted in 100 g of dry chloroform at room temperature for 48 hours. The reaction mixture was then filtered and the zeolite was thoroughly washed with chloroform. Combine the washing solution and dilute with methanol, pass through an Amberlite 200C column, and add DMA.
P was excluded. Purified in the same manner as Example-1, and D P P
85 g of C2 was obtained.

Example-4 10 g of the GPC methanol solution obtained in Reference Example-2 was
In addition to 10 g of finely crushed granular activated carbon, GPC was impregnated while removing methanol in an evaporator. Next, benzene was added and azeotropic dehydration was performed under reduced pressure to completely remove water and methanol. This GPC-impregnated activated carbon, 12.8 g (0,0235 mol) of oleic anhydride obtained in Reference Example-3, and 2.2 g (0,0176 mol) of D M A P
The reaction mixture was then filtered, and the activated carbon was thoroughly washed with chloroform. Combine the washing solution and dilute with methanol, pass through an Amberlite 200C column, and DM
AP was excluded. Purification was carried out in the same manner as in Example 2 to obtain 3.41 g of phosphatidylcholine dioleate (DOPC).

Example 5 10 g of the GPC methanol solution obtained in Reference Example 2 was added to glass beads Log having a diameter of 0.5 square meters or less, and impregnated with GPC while removing methanol in a vaporizer.

Next, benzene was added and azeotropic dehydration was performed under X pressure to completely remove water and methanol. These GPC-impregnated glass beads and 12.8 g of oleic anhydride (0,0
235 mol) and DMA P2.2 g (0,0176
mol) in 100 g of dichloromethane at room temperature for 48 hours.Then, the reaction mixture was filtered, and the glass beads were thoroughly washed with dichloromethane. The washing solution and the solution were combined, diluted with methanol, and passed through an Amberlite 200C column to remove DMAP. Purification was performed in the same manner as in Example-1 to obtain 2.96 g of DOPC.

Example 6 GPC-impregnated zeolite obtained in the same manner as in Example 3 and commercially available balmitic acid chloride were reacted using pyridine as a catalyst.

That is, GPC-impregnated zeolite with 50 g of dichloroformmethane
6.5 g of balmitic acid chloride (
0°0235 mol) was dissolved in 25 g of dichloromethane,
Slowly dropped 6 then pyridine, 4 g (o, ot
7 s mol) was dissolved in 25 g of dichloromethane and added dropwise. The reaction was carried out for 30 minutes and then at room temperature for 2 hours. The reaction mixture was filtered and the zeolite was thoroughly washed with dichloromethane. Combine the washing solution and the solution, concentrate, and add 200 ml of acetone at -20°C.
mΩ to obtain a precipitate. Purification was performed in the same manner as in Example-1 to obtain DPPC2, 14 g.

Example-7 The GPC-impregnated activated carbon obtained in the same manner as in Example-4 was reacted in the same manner as in Example-6 to obtain 2.25 g of MIBLDPPC.

Example-8 40 g of the crude GPC methanol solution obtained in Reference Example-1 was added to 40 g of dried commercially available styrene-divinylbenzene resin (beads), and while methanol was removed in an evaporator, the crude GPC was impregnated into the resin. Benzene was then added and azeotropic dehydration was performed under reduced pressure to completely remove water and methanol. 10 g of this crude GPC-impregnated resin was taken and reacted in the same manner as in Example-1.Then, the reaction mixture was filtered, and the resin was thoroughly washed with dichloromethane. Combine the cleaning solution and the solution, dilute with methanol, and add Amberlite 200.
DMAP was removed by passing it through a column of C. Purification was performed in the same manner as in Example-1 to obtain 65 g of D P P C1.

Example-9 Using the crude GPC-impregnated resin tog obtained in Example-8, a reaction was carried out in a mixed solvent of 70 g of dichloromethane and 30 g of dimethylacetamide in the same manner as in Example-1. The reaction mixture was then filtered and the resin was washed thoroughly with dichloromethane. The washing solution and the solution were combined, diluted with methanol, and passed through an Amberlite 200C column to remove DMAP.

Purification was performed in the same manner as in Example-2 to obtain 18 g of DPPC2.

Example-10 10 g of the crude GPC-impregnated resin obtained in Example-8, 5.6 g (0,022 mol) of valmitic acid, and 6.8 g of DCC (
0,033 mol), DMAPo, 89 g (0,0073
After the reaction, the reaction mixture was filtered and the resin and dicyclohexylurea were washed with dichloromethane. Combine the washing solution and the solution, dilute with methanol, pass through an Amberlite 200C column, and add DMAP.
was excluded. Purified in the same manner as in Example-1, DPPC2,2
6g was obtained.

Example-11 Crude GPC methanol solution 4 obtained by the method of Reference Example-1
0 g was added to 40 g of Celite, and while methanol was removed using an evaporator, crude GPC was impregnated into Celite, and methanol and water were completely removed by azeotropic dehydration with benzene. 10 g of this crude GPC celite was taken and reacted in the same manner as in Example-1.

Then, the reaction mixture was filtered and the Celite was thoroughly washed with dichloromethane. Combine the washing solution and solution, dilute with methanol, and pass through an Amberlite 200C column for DMA.
P was excluded. Purified in the same manner as in Example-1, DPPC1,
2g was obtained.

Example-12 Crude GPC methanol solution 3 obtained by the method of Reference Example-1
0g was added to 30g of activated clay, 10g of the crude GPC-impregnated activated clay obtained in the same manner as in Example-11 was taken, and reacted in the same manner as in Example-1.

After removing DMAP in the same manner as in Example-11, the product was purified in the same manner as in Example-1 to obtain 1.4 g of DPPC.

Agent Patent attorney Yanagi Hara Written amendment April 1985, Japan Patent Application No. 48646, filed in 1985 2, Title of invention Method for producing phosphatidylcholine 3, Relationship with the person making the amendment Case Patent applicant representative Ogawa Terutsugu 4, agent 105 telephone number 436-47006, amend column 7 of the detailed explanation of the invention of the specification subject to amendment and page 8 of the specification of contents of the amendment as shown in the attached sheet.

This is a method for obtaining PC, and the reaction is performed using the following reaction formula (in the formula, RCO- represents an acyl group) [Problems to be solved by the invention]

Claims (5)

[Claims] (1) A method for producing phosphatidylcholine, which comprises mixing glycerophosphorylcholine adsorbed or impregnated onto a carrier and activated fatty acid in a solvent in the presence of a catalyst and reacting the same. (2) The manufacturing method according to claim 1, wherein the carrier is silica gel, activated carbon, zeolite, glass, earthenware, porcelain, celite, activated clay, rock, or resin. (3) The production method according to claim 1 or 2, wherein the activated fatty acid is an anhydride, a chloride, or an imidazolate of a natural or synthetic saturated or unsaturated fatty acid having 8 to 24 carbon atoms. (4) The solvent is dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone,
Claim 1 contains hexamethylphosphoramide, sulfolane, or tetramethylurea.
The manufacturing method according to any one of Items 1 to 3. (5) The production method according to claim 3, wherein the fatty acid anhydride is synthesized using a fatty acid and a carbodiimide condensing agent in an amount equal to or more than the same molar amount as the fatty acid during the synthesis of phosphatidylcholine.