JPH0421691A - Production of phosphatidylcholine derivative and its analog and their intermediate - Google Patents

Abstract

PURPOSE:To easily obtain the subject derivative useful as a raw material for liposome, etc., by reacting a specific compound with phosphorus oxyhalide, reacting the reaction product with a specific compound in the presence of a tertiary amine, and reacting with water in the presence of a basic substance. CONSTITUTION:The objective compound of formula IV can be produced by reacting a compound of formula I (R<1> is 10-24C alkyl) with a phosphorus oxyhalide to obtain a compound of formula II (X is halogen), reacting the compound with a compound of formula III (R<2> is lower alkyl; Y<-> is sulfuric acid ion, alkylsulfuric acid ion or sulfonic acid ion; (n) is 2-10) in the presence of a tertiary amine, and finally reacting the product with water in the presence of a basic substance.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing a phosphatidylcholine derivative useful as a material for liposomes, and intermediates thereof.

[Prior Art] Methods for producing phosphatidylcholine crocodile conductors can be roughly divided into two methods: a method in which a glycerophosphatidylcholine derivative is used as a raw material and diacylated, and a method in which a diacylated glycerol is used as a raw material and a choline group is introduced therein.

Among these, as a method for synthesizing phosphatidylcholine derivatives using diacylated glycerol as a raw material,
gs Ann, Ches+, 709, 226-230
(1967) is known.

As shown in the reaction formula below, this method condenses 2,2-diacylated glycerol and β-bromoethyl cyclophosphate to synthesize β-bromoethyl 1,2-diacylated glycerol monochlorophosphate, which is then hydrolyzed. dechlorinated and 1,2-diacylated glycerol-phosphate β
- bromoethyl ester, condensation of this with trimethylamine to obtain phosphatidylcholine hydrobromide, and dehydrobromide with silver carbonate.

CH20COR CH20COR CH20COR C)120COR H H ↓A8. C03 CH20COR CH0COR CH20PO2CH2CH2N"(CH3)3 [Problem to be solved by the invention] However, the trimethylamine used in this method has a boiling point (
(4°C) is extremely low, it evaporates outside the reaction system during the condensation reaction, causing environmental pollution problems. Also, the use of silver carbonate in the final stage of synthesis poses various problems. That is, when the obtained phosphatidylcholine derivatives are used as raw materials for liposome formulations of pharmaceuticals, extremely strict purification is required to prevent residual silver compounds. This requires a complicated operation of recovering silver ions from the waste liquid produced during this process.

An object of the present invention is to solve this problem and provide a simple method for producing phosphatidylcholine derivatives.

[Means for Solving the Problems] In order to solve the above problems, the present inventors have conducted intensive research into a new method for producing phosphatidylcholine derivatives, and as a result, have discovered a simple method that does not use trimethylamine or silver compounds. The invention was completed.

In the present invention, phosphorus oxyhalide is reacted with a compound represented by the formula [I1% formula% [] (wherein R1 represents a linear or branched alkyl group having 10 to 24 carbon atoms). Then, in the presence of a tertiary amine, a compound represented by the formula [I1] % formula % (wherein, X represents a halogen atom, and R1 is the same as above),
Formula [■KOHO(CH2)-N"R-Y-[ml (wherein, R2 represents a lower alkyl group, Y- represents a sulfate ion, an alkyl sulfate ion, or a sulfonate ion, and n is 2- (represents an integer of 10) is reacted, and then,
Reacted with water in the presence of a basic substance, formula [IV] CH
This invention relates to a method for producing a phosphatidylcholine derivative represented by 20COR1 (wherein R+, R2 and n are the same as above).

Further, the present invention provides the formula [I1] %formula% (In the formula, R1 and X are the same as above.) This is an invention of a compound represented by

That is, the present invention introduces a dihalogenophosphoryl group into the hydroxyl group of 1,2-diacylated glycerol, and replaces one of the halogen atoms with an alcohol that has been converted into a quaternary ammonium salt in advance to achieve 1,2-diacylated glycerol. Invention of a method for producing a phosphatidylcholine derivative, which involves forming a monohalokenophosphate of glycerol and treating this with water in the presence of a basic substance to simultaneously perform a dehalogenation reaction and intramolecular salification, and an intermediate for the method. This is an invention of a compound that becomes

The present invention will be explained in detail below.

First, to explain the compound represented by the above formula,
The compound represented by formula [I] has a glycerol skeleton of 2-
It has an asymmetric carbon at the position, and there are 0-isomers and L-00 optical isomers, and the method of the present invention can be carried out using either of them or a mixture thereof. Applicable. In the formula [I1, R1 is not particularly limited as long as it is an alkyl group having 10 to 24 carbon atoms. Chain alkyl group, butylhexyl group, trimethylundecyl group, (trimethylbutyl)trimethylhebutyl group, heptyldecyl group,
Examples include branched furkyl groups such as dibutyldodecyl groups.

R1 in formula [I1] can be exemplified by the same group as in formula [I], and X in formula [I1] is the same halogen atom as the phosphorus oxyhalide used in its construction.

R2 in formula [I11] is, for example, a methyl group, an ethyl group, a propyl group, or an isopropyl group.

Butyl group, isobutyl group, 5ec-butyl group and te
Examples of Y include lower alkyl groups such as r-butyl group, and examples of Y include alkyl sulfate ions such as sulfate ion, methyl sulfate ion, and ethyl sulfate ion, methanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, Examples include aliphatic or aromatic sulfonate ions such as p-toluenesulfonate ion, and particularly preferred are alkyl sulfate ions and aromatic sulfonate ions. Furthermore,
n in formula [I11] is an integer of 2 to 10,
An integer of 2 to 5 is more preferred, and 2 or 3 is particularly preferred.

R1. R2 and n are formula [I].

The same groups as in the case of formula [I1] and formula [ml can be exemplified.

Among the compounds represented by the above formulas, the method for producing the compound represented by formula [I] is described in J. Chem, Soc, 1951.
2663, and the method for preparing the compound represented by the formula [ml] is described in Chem, Phars, Bu 11.
．． 37.1249 (1989),
It may be manufactured according to these.

Next, the manufacturing method of the present invention will be explained.

First, the compound represented by formula [I1] is prepared by mixing the compound represented by formula [I1] and phosphorus oxyhalide at a fixed charging ratio, and stirring the mixture at a prescribed temperature for a prescribed time. It is preferable to use a suitable solvent and to add a tertiary amine to accelerate the reaction.

Examples of the phosphorus oxyhalide used in this reaction include phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyfluoride, and phosphorus oxyiodide, with phosphorus oxychloride being particularly preferred. In addition, there are no particular restrictions on its usage, but
In order for the reaction to proceed completely, it is necessary to use the compound in an amount equal to or more than the equivalent mole of the compound represented by formula [I1]. Usually, in order to suppress the residual phosphorus oxyhalide in the next step as much as possible, a molar excess of about 0.01 to 0.05 times is used. Mixing a compound of the formula [I] with a phosphorus oxyhalide produces a compound of the formula [IF
This is done by gradually adding the compound shown in . When a solvent is used, a method in which a solution of the compound represented by formula [I] is added dropwise is adopted, which is particularly preferred since the reaction proceeds smoothly. In this case, only the compound represented by formula [I1] may be dissolved, or both the compound represented by formula [I] and the phosphorus oxyhalide may be dissolved respectively. Any solvent that can be used may be used as long as it dissolves the raw materials and does not react with itself. Specific examples include halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and chlorohenzene. hydrogenated hydrocarbons, Hensen.

Aromatic hydrocarbons such as toluene and xylene, diethyl ether, tetrahydrofuran, and dioxane.

Ethers such as ethylene glycol dimethyl ether,
Esters such as ethyl acetate, formamide.

Amides such as N,N-dimethylformamide are mentioned, halogenated hydrocarbons are more preferred, and chloroform is particularly preferred. Moreover, even if these solvents are used alone,
Two or more types may be mixed and used.

The amount of these solvents to be used depends on the amount that can dissolve the raw materials,
In addition, there is no particular restriction as long as the amount does not extremely reduce the reaction rate, but it is usually used in a total amount of 3 to 20 L per mol of the compound represented by formula [I], and preferably, It is 5-15L.

The temperature of this reaction may be as long as the reaction can proceed without any problems, but as with general chemical reactions, side reactions can be avoided at lower temperatures; for example, it is carried out in the range of -20 to +40°C. is preferable. In addition, in order to make this reaction proceed smoothly at low temperature, it is effective to add a tertiary amine.
A specific example of the tertiary amine that can be added is triethylamine.

Examples include N,N-dimethylaniline and pyridine,
Particularly preferred is triethylamine. The amount used may be in excess of the compound represented by formula [I], but in order to make the reaction proceed more smoothly, it is usually used in an amount of 2 to 10 moles per mole of phosphorus oxyhalide. Ru. Regarding the timing of addition of the tertiary amine, it may be added dropwise during the reaction, but it is more effective to add it from the beginning.
It may be preferentially mixed with any of the compounds shown above and phosphorus oxyhalide. The reaction progresses by, for example, mixing a part of the reaction solution with an appropriate alcohol to esterify the product, converting it into a stable compound, and then, for example,
It can be easily observed by thin layer chromatography or the like.

After completion of the reaction, the product may be isolated and purified by performing usual operations such as concentration, redissolution, filtration, and crystallization, but in order to simplify the operation and avoid decomposition of the product, etc. Also, the reaction solution is usually used in the next step without isolation.

Next, the production of the phosphatidylcholine derivative represented by the formula [IV], which is the object of the present invention, is carried out by adding the above-described compound to the solution of the compound represented by the formula [n] in the presence of a tertiary amine. This is carried out by gradually adding a compound represented by the formula [■], reacting at a predetermined temperature for a predetermined time, and then treating with water in the presence of a basic substance.

Examples of the type and amount of the solvent for dissolving the compound represented by formula [I[] are the types and amounts of solvents listed in the explanation of the method for producing the compound represented by formula [II]. . Therefore, when the reaction solution from the previous step is used as it is, there is no need to add any new solvent and no operation for dissolution is required. The amount of the compound represented by formula [III] to be used is not particularly limited as long as it is in excess of the compound represented by formula [I].
It is used in an amount of 1 to 2 mol per 1 mol of the compound represented by I11. In addition, when the reaction solution from the previous step is used as it is, the number of moles of the compound represented by formula [I1], which is the basis for calculating the usage amount of the compound represented by formula [III], is based on the raw material from the previous step. The number of moles of a compound represented by a certain formula [I1 can be used.

Specific examples of tertiary amines that should be present during the reaction include:
Examples include triethylamine, N,N-dimethylaniline and pyridine, with pyridine being particularly preferred. Further, the amount thereof may be in excess of the compound represented by formula [I11]. In addition, when dropping the compound represented by the formula [ml] as a solution, it is possible to use any of the solvents exemplified in the explanation of the method for producing the compound represented by the formula [I1]; In order to avoid a harsh solvent system, it is preferable to use this tertiary amine as a solvent. In that case,
The minimum amount of tertiary amine necessary for dissolution is used, but the amount depends on the type of amine and the type of compound represented by formula [ml], for example, 200 times or more the weight of the compound represented by formula [I11]. In some cases, it reaches . Also, in the previous process,
When using an excess of tertiary amine compared to the compound represented by formula [I], if the compound represented by formula [I1] is used as the reaction solution from the previous step, a certain amount of tertiary amine has already been used. Since the tertiary amine is already present, the amount of tertiary amine added in this step is sufficient to compensate for the shortage, and if it is already present in sufficient quantity, there is no need to add any more.

The temperature of this reaction is also not particularly limited, as long as the reaction can proceed without any problem, as in the case of producing the compound represented by formula [I1], but a low temperature is preferable, for example -2
The temperature range is 0 to +40°C.

The progress of the reaction can be easily observed by thin layer chromatography.

Examples of basic substances to be added together with water after the condensation reaction are hydroxides of alkaline earth or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, sodium carbonate, potassium carbonate, and calcium carbonate. carbonates of alkali metals or alkaline earth metals such as, alkali metal hydrogencarbonates such as sodium bicarbonate and potassium bicarbonate, tertiary amines such as triethylamine, N,N-dimethylaniline and pyridine, etc. Alkali metal bicarbonates are preferred. There is no particular restriction on the amount of water and basic substance used as long as it is equimolar or more than the compound represented by the formula [II[] used, but usually water and the amount of water about,
5 to 500 times the molar amount, and for basic substances, 2 to 500 times the molar amount.
It is 100 times the molar amount. In addition, the tertiary amine that was present when reacting the compound represented by formula [I11] was replaced by the compound represented by formula [m
] If the amount of the basic substance is in excess of the compound represented by , the amount of the basic substance added may be reduced or the addition itself may be omitted depending on the remaining amount.

After hydrolysis, the desired phosphatidylcholine derivative solution can be obtained by separating the aqueous layer, concentrating the organic layer, and subjecting it to column chromatography using an appropriate solvent.
This includes concentration, precipitation, crystallization, etc., as usual! All you have to do is perform the i operation. The obtained phosphatidylcholine derivative can be further purified by recrystallization, recrystallization, column chromatography, etc., if necessary.

Examples are given below, but the present invention is not limited to the same extent by these Examples. In addition, the compounds represented by the formulas [I, [II], [m] and the formula [
IV] yield of phosphatidylcholine derivative,
The measurement results of melting point, IR, NMR, and specific rotation are shown in Table 1.
2 and 3 are listed together.

[Example] Reference Example 11. Production of 2-diacylated glycerol (1)
Racemic form of the compound DL-2,3-isopropylidene glycerol 66.1 of the compound where R1=n-C15)131 in formula []
Dissolve g (0,5*ol) in 400ml of toluene, add 11.5g (0,5*ol) of metallic sodium,
The mixture was stirred and refluxed. After 2 hours, Hensyl Bromide 85.5
g (0,5-01) was added dropwise over a period of 1 hour, followed by IR reflux.

After the reaction was completed, the resulting solution was filtered to remove insoluble matter and distilled under reduced pressure to obtain 93.8 g of DL-2,3-isopropylidene glycerol-1-benzyl ether (yield: 8
4.4%). Furthermore, its 80.0g (0,36*ol
) was deprotected by refluxing in a 10% (v/v) acetic acid aqueous solution 2001 for 2 hours, and distilled under reduced pressure to obtain 54.6 g 1 t of DL-glycerol-]-hensyl ether (yield 83
．． 2%).

Then, 50.0 g (0.27*ol) of the obtained DL-glycerol-1-hensyl ether and 43.0 g of pyridine.
4g (0,54-ol) in 340ml of carbon tetrachloride
A solution of 150 g (0.54 ml) of balmitoyl chloride dissolved in 100 ml of carbon tetrachloride was added dropwise at room temperature with stirring, and the mixture was further stirred at 40° C. for 4 hours. After removing the precipitated salt, the solvent was distilled off and D
158 g of white crystals of L-3~hensyl-1,2-dipalmitoylglycerol were obtained (yield: 87.6%).

Furthermore, 150 g (0,23*ol) of the obtained crystals were added to n
-Hydrogenate in 1200 ml of hexane using palladium black as a catalyst at room temperature, filter off the catalyst while hot, and crystallize.
122 g of white crystals of compound 1) were obtained (yield 94.1%).
).

(2) In formula [I], R' = n-c15"3+
T: DL-2,3-isopropylideneglycerol in optically active form (1) of a certain compound is replaced with D-2,3-isopropylideneglycerol and L-2,3-isopropylideneglycerol (1) The corresponding 1 and 2 dipalmitoylglycerols (compounds 2 and 3) were obtained in the same manner as above.

(3) In formula [I], R' = n-c17)135
and racemic and optically active forms of the compound where n-C13■27, and R'=R'R''CH(R''(CH3)
CHCH2(C)+3)C)lcH2c)+2. R”＝
(CH3-3CC)+2(C)+3>C)l Racemic form of the compound (1) and (2) were treated in the same manner as in (1), replacing balmitoyl chloride with stearoyl chloride and myristoyl chloride, respectively. , 1,2-diacylated glycerol (compounds 4 to 9) corresponding to each other were obtained.

In addition, balmitoyl chloride in (1) is replaced with 2-(1
, 3,3-)limethylbutyl)-5,7,7-drimethyloctanoyl and the corresponding DL-1,2-diacylated glycerol (compound 10
) was obtained as a viscous liquid.

Margin reference example 2 below. Production of hydroxyalkyl quaternary ammonium salt (1) In formula [■, R2=CH3, n=2, Y=ρ
- toluenesulfonate ion, benzenesulfonate ion, methanesulfonate ion and methylsulfate ion, the compound 2-hydroxy-N,N-dimethylethylamine 4.5 g (0.05 mol) and p-)methyl toluenesulfonate 9 3 g (0.05 i+ol) was dissolved in 501 toluene and stirred at room temperature for 2 hours. After the reaction is completed, the precipitated product is a! and N-(2-hydroxy 1
11.43 of white crystals of methyl ammonium p-toluenesulfonate (compound 11) were obtained. Yield 82.8%.

In addition, the same treatment was carried out by replacing methyl p-)luenesulfonate with methyl benzenesulfonate, methyl methanesulfonate, and dimethyl sulfate, respectively, to obtain the corresponding hydroxyalkyl quaternary ammonium salts (compounds 12 to 4). .

In addition, when dimethyl sulfate was used, the product was obtained in the form of a liquid, and the reaction solution was simply concentrated.

(2) In formula [■, R2 = C) 13c) 12, Y
-=p-) luenesulfonate ion, compound 2-hydroxy-N,N-diethylethylamine with n=2 5.9
8 (0.05 mol) and 10.13 (0.05 mol) of ethyl p-toluenesulfonate were dissolved in xylene 501 and stirred for 5 hours. After the reaction, the solvent was distilled off under reduced pressure and N,N,N-)riethyl-N-(2-hydroxyethyl)ammonium p-toluenesulfonate (
15.6 g of compound 15) was obtained as a pale yellow oil. Yield 98.0%.

(3) 2-hydroxy-N,N-dimethylethylamine in compound (1) where R2=CH3, y-=p-toluenesulfonic acid ion, n=3 in formula [■] , Substituting N-dimethylpropylamine and treating in the same manner as in (1), white crystals of N-(3-hydroxypropyl)-N,N,N-)limethylammonium p-)luenesulfonate (compound 16) were obtained. s, og was obtained. Yield 55.0%.

Example 1. Preparation of dichlorophosphate ester of DL-1,2-dipalmitoylglycerol (racemic compound of the formula [■, where R' = n-clsH31, X = CI) 3.1 g of phosphorus oxychloride ( 20 mmol) and triethylamine 10.23 (100**ol) dissolved in chloroform 601, a solution of compound 11.1 g (2 ml Io I) dissolved in the same solvent 15-1 was added to a solution of 11.1 g (2 ml Io I ) of the same solvent at 0° C. for 1 hour with stirring. It took 30 minutes to drip, and then another 3 to 2
The mixture was stirred at 0°C for 3 hours. Next, the residue was concentrated under reduced pressure at 50°C, and then redissolved in diethyl ether 50-1 to remove insoluble matter. The solvent was again completely distilled off under reduced pressure to obtain 1.38 g of dichlorophosphoric acid ester of DL-1,2-dipalmitoylglycerol as a yellow-brown waxy solid. Yield 100%.

Melting point: 32-53°C I Rj;;! i'A: v cta' 2940
．． 2860.1755.1475゜' H-N M R
(CDCI 3): δpp+n O, 88 (t, 6)
1. C, 1.26 (S, 48H, (CH2)l
2), 1.62 (Im, 4H, C0CH2C and 2), 2
．． 32(s+, 4)1. C0Cj12), 3.66(-
, 2H, C-dan. -0P03), 4.22.4.35(s
, 2H, CH, 0CO), 5.23 (w, 01.C and) Example 2. DL-dipalmitoylphosphatidylcholine (in formula [IV], R' = n-C15H3, R2 =
Production of a racemic compound (CH3, n=2) 6.9 g (10°2
s + mol) was dissolved in chloroform 1051, and 114.0 g (14,5 mol) of the compound was dissolved in pyridine 1401.
+w+wol) was added dropwise under stirring at 0° C. over 1 hour, and the mixture was further stirred at room temperature.

After 12 hours had passed, 76.7 g of water in which 6.78 of sodium hydrogen carbonate had been dissolved was added, and after stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel as an adsorbent,
4.78 g of white crystals of D,L-dipalmitoylphosphatidylcholine (compound 17) were obtained.

Yield 64.3%.

Example 3. A solution of 15.7 g (10*mol) of the compound dissolved in the same solvent 701 was added to a solution of 1.568 (Io, 2 m*ol) of the same phosphorus oxychloride and 5.063 (50+wmol) of triethylamine dissolved in 35 ml of chloroform. The mixture was added dropwise over 1 hour at 0° C. with stirring, and further stirred at room temperature for 1 hour.

Then compound II was added to pyridine 1401 4. (Ig
(14,5+mmol) was dissolved in a solution of 0.0
The mixture was added dropwise over a period of 1 hour at ℃ and further stirred at room temperature.

After 12 hours had passed, 76.73 ml of water in which 6.78 ml of sodium hydrogen carbonate had been dissolved was added, and after stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel as an adsorbent,
4.68 g of white crystals of Compound 17 were obtained. Yield 62.6%
.

Example 4. Compound 11 in Example 3 above was replaced with Compounds 12 to 14, respectively, and the same treatment as in Example 3 was performed, each yielding 59.9%.

Compound 17 was obtained with yields of 9.5% and 65.4%.

Example 4. Production of various diacylated phosphatidylcholines Compound 1 in Example 3 was replaced with compounds 2 to 10, and the same procedure as in Example 3 was carried out to obtain the corresponding diacylated phosphatidylcholines (compounds 18 to 26). Note that Compound 26 was obtained as a paste-like substance at room temperature.

Example 5. Compound 11 in Example 3 above was replaced with compounds 15 and 16, respectively, and the same treatment as in Example 3 was carried out to obtain the corresponding diacylated phosphatidylcholine analogues (compounds 27 and 28).
I got it.

E Effects of the Invention The present invention provides a method for producing phosphatidylcholine derivatives that does not cause environmental pollution and can be easily carried out by avoiding the use of low boiling point raw materials such as trimethylamine and heavy metal compounds such as silver compounds. This invention has a remarkable effect in that it provides a method.

Patent applicant: Wako Pure Chemical Industries, Ltd. May 2, 1991

Claims (1)

[Claims] 1. Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a linear or branched alkyl group having 10 to 24 carbon atoms.) The compound represented by is reacted with phosphorus oxyhalide to form the formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, X represents a halogen atom, and R^1 is the same as above. ), and in the presence of a tertiary amine, to this,
Formula [III] HO(CH_2)_nN^+R^2_3・Y^-[III
] (In the formula, R^2 represents a lower alkyl group, Y^- represents a sulfate ion, an alkyl sulfate ion, or a sulfonate ion, and n represents an integer of 2 to 10.) , then react with water in the presence of a basic substance, formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] (In the formula, R^1, R^2 and n are the same as above. .) A method for producing a phosphatidylcholine derivative. 2. Formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^1 represents a linear or branched alkyl group having 10 to 24 carbon atoms, and X represents a halogen atom. ), in the presence of a tertiary amine, the formula [III] HO(CH_2)_nN^+R^2_3・Y^-[III
] (In the formula, R^2 represents a lower alkyl group, Y^- represents a sulfate ion, an alkyl sulfate ion, or a sulfonate ion, and n represents an integer of 2 to 10.) , then react with water in the presence of a basic substance, formula [IV] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [IV] (In the formula, R^1, R^2 and n are the same as above. ) A method for producing a phosphatidylcholine derivative. 3. Claim 1, wherein R^1 is a linear alkyl group having 13 to 17 carbon atoms, R^2 is a methyl group, and n is 2.
Or the method described in 2. 4.Claim 1, 2 or 3, wherein X is a chlorine atom and Y^- is an alkyl sulfate ion or an aromatic sulfonate ion.
Method described. 5. Formula [II] ▲Mathematical formulas, chemical formulas, tables, etc.▼[II] (In the formula, R^1 represents a linear or branched alkyl group having 10 to 24 carbon atoms, and X is a halogen atom. ). 6. The compound according to claim 5, wherein X is a chlorine atom.