Phosphocholine compound containing nitrogen-containing heterocyclic ring, production method therefor, and method for producing phosphocholine derivative

Abstract

The present invention provides: a compound with which it is possible to easily introduce a phosphocholine group into a hydroxyl group of a compound serving as a substrate, without using phosphorus oxychloride or trimethylamine; and a method for producing said compound.　This compound is a phosphocholine compound containing a nitrogen-containing heterocyclic ring and is represented by general formula (1). [Chemical formula 1] (In the formula, A is selected from the structural formulae.) [Chemical formula 2] (In the structural formulae, Ra and Rb each independently represent a C1-C22 alkyl group, an alkenyl group, or an alkynyl group, R1, R2, R3, R4, R5, R6, R7, R8, and R9 each independently represent a C1-C12 alkyl group, and symbol * indicates a bond.)

Description

Nitrogen-containing heterocycle-containing phosphocholine compound, method for producing the same, and method for producing phosphocholine derivative

[0001] The present invention relates to a nitrogen-containing heterocycle-containing phosphocholine compound and a method for producing the same, as well as a method for producing a phosphocholine derivative.

[0002] In vivo, compounds having a phosphocholine group, such as phosphatidylcholine, sphingomyelin, and glycerophosphocholine, exist, and these play important roles in biological activities. Furthermore, compounds having a phosphocholine group are used as active ingredients in pharmaceuticals and topical skin preparations (e.g., Patent Documents 1 and 2), and in the field of medical materials, attempts have been made to introduce a phosphocholine group into polymeric compounds in order to improve their biocompatibility (e.g., Patent Document 3).

[0003] To produce a compound having a phosphocholine group (phosphocholine derivative), it is necessary to introduce the phosphocholine group into the hydroxyl group of a substrate compound having a hydroxyl group via a phosphate ester bond. Common methods for introducing the phosphocholine group include reacting a compound having a hydroxyl group with 2-chloro-1,3,2-dioxaphospholane-2-oxide to form a cyclic phosphate ester, which is then ring-opened with trimethylamine (Patent Document 3), and reacting a compound having a hydroxyl group with phosphorus oxychloride, followed by reaction with a choline salt and subsequent hydrolysis (Patent Document 4). However, a method that does not use trimethylamine, a malodorous substance, or phosphorus oxychloride, an irritant, is desired. While several other methods for introducing the phosphocholine group are known, including the above methods, all require a multi-step reaction process using a substrate as a starting material, making them complicated. Therefore, a simpler method for introducing the phosphocholine group is desired.

[0004] Japanese Patent Application Laid-Open No. 2009-234945 Japanese Patent Application Laid-Open No. 62-126108 International Publication No. 2004 / 074298 Japanese Patent Application Laid-Open No. 05-186483

[0005] The object of the present invention is to provide a compound that can easily introduce a phosphocholine group into the hydroxyl group of a substrate compound without using phosphorus oxychloride or trimethylamine, and to provide a method for producing the compound.

[0006] Another object of the present invention is to provide a method for simply producing a compound (phosphocholine derivative) in which a phosphocholine group has been introduced into the hydroxyl group of a compound having a hydroxyl group, without using phosphorus oxychloride or trimethylamine.

[0007] As a result of intensive research to solve the above problems, the present inventors discovered that a nitrogen-containing heterocycle-containing phosphocholine compound represented by the following general formula (1) can solve the above problems, and thus completed the present invention. (wherein A is selected from the following structural formulas): (In the above structural formula, R ａ and R ｂ each independently represents an alkyl group, an alkenyl group, or an alkynyl group having 1 to 22 carbon atoms; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ each independently represents an alkyl group having 1 to 12 carbon atoms, and * indicates a bond.

[0008] Furthermore, the inventors have found that the nitrogen-containing heterocycle-containing phosphocholine compound represented by the general formula (1) can be produced by reacting a compound represented by the following general formula (I) with a compound represented by the following general formula (II), thereby completing the present invention. (In the formula, A has the same meaning as A in the general formula (1) above.)

[0009] In addition, the present inventors have discovered a method for producing a compound (phosphocholine derivative) in which a phosphocholine group has been introduced into the hydroxyl group of a nitrogen-containing heterocycle-containing phosphocholine compound represented by the general formula (1) by reacting the compound with a hydroxyl group, thereby completing the present invention.

[0010] The nitrogen-containing heterocycle-containing phosphocholine compound of the present invention can be reacted with a substrate compound having a hydroxyl group to introduce a phosphocholine group into the hydroxyl group of the substrate in a one-step reaction.

[0011] Furthermore, according to the method for producing a phosphocholine derivative of the present invention, the phosphocholine derivative can be produced in a one-step reaction by reacting the nitrogen-containing heterocycle-containing phosphocholine compound of the present invention with a compound having a hydroxyl group as a substrate.

[0012] <Nitrogen-containing heterocycle-containing phosphocholine compound> The nitrogen-containing heterocycle-containing phosphocholine compound of the present invention (hereinafter also simply referred to as phosphocholine compound) is a compound represented by the following general formula (1). (wherein A is selected from the following structural formulas): (In the above structural formula, R ａ and R ｂ each independently represents an alkyl group, an alkenyl group, or an alkynyl group having 1 to 22 carbon atoms; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ each independently represents an alkyl group having 1 to 12 carbon atoms, and * indicates a bond.

[0013] The compound represented by general formula (1) is a compound having a structure in which the phosphorus atom of phosphocholine and the nitrogen atom of a nitrogen-containing heterocyclic compound are covalently bonded. A in general formula (1) is selected from the structural formulas (a) to (t) above, and in addition to having a nitrogen-containing heterocyclic structure, these have in common the fact that they are five-membered rings and that the only heteroatom forming the ring is a nitrogen atom. From the viewpoint of further exerting the effects of the present invention, A in general formula (1) is preferably selected from the structural formulas (c), (d), (e), (f), (g), (m), (n), (o), (p), and (q), and more preferably selected from the structural formulas (c), (d), (m), and (n). R in the structural formula of A ａ and R ｂis preferably an alkyl group, alkenyl group, or alkynyl group having 1 to 12 carbon atoms, and more preferably an alkyl group having 1 to 12 carbon atoms. １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ is preferably an alkyl group having 1 to 8 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms.

[0014] The method for producing the phosphocholine compound of the present invention is not particularly limited, and it may be produced by a generally known method. However, from the viewpoint of more efficient production, the phosphocholine compound of the present invention is preferably produced by the following method.

[0015] <Method for Producing Phosphocholine Compound> The phosphocholine compound represented by the general formula (1) can be produced by reacting a compound represented by the following general formula (I) with a compound represented by the following general formula (II). (In the formula, A has the same meaning as A in the general formula (1) above.)

[0016] The compound represented by general formula (I) used in the method for producing a phosphocholine compound of the present invention is a compound commonly known as phosphocholine. The compound represented by general formula (I) used in the present invention may be in the form of a salt. A commercially available compound represented by general formula (I) can be used. Commercially available compounds are generally aqueous solutions or hydrates, but from the standpoint of yield and economy, it is preferable to use a dehydrated compound. Examples of dehydration methods include azeotropy with an organic solvent capable of azeotroping with water, or reaction with a dehydrating agent in the presence of an acid catalyst. The organic solvent capable of azeotroping with water is not particularly limited, but toluene and methoxyethanol can be used. The dehydrating agent is not particularly limited, but orthoesters can be used. It is more preferable to use a compound dehydrated by the above method and then powdered by recrystallization or grinding.

[0017] The compound represented by general formula (II) used in the method for producing a phosphocholine compound of the present invention is a carbonyl compound having two nitrogen-containing heterocycles. The two A structures in the compound represented by general formula (II) may be the same or different, but are preferably the same. The compound represented by general formula (II) used in the present invention may be in the form of a salt. The compound represented by general formula (II) can be a commercially available compound, or can be obtained by a commonly known production method, for example, by reacting a nitrogen-containing heterocycle compound having the structural formula A (a compound in which the bond in the structural formula A is bonded to a hydrogen atom) with phosgene.

[0018] In the method for producing a phosphocholine compound of the present invention, the reaction ratio of the compound represented by general formula (I) to the compound represented by general formula (II) is preferably 1 to 10 moles, preferably 1.5 to 8 moles, more preferably 2 to 6 moles, of the compound represented by general formula (II) per 1 mole of the compound represented by general formula (I), from the viewpoints of yield and economy.

[0019] In the method for producing a phosphocholine compound of the present invention, the reaction can be carried out in the presence of a base in order to further promote the progress of the reaction. Specific examples of the base to be used include organic bases such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, tetramethylguanidine, imidazole, N-methylimidazole, triazole, tetrazole, pyridine, dimethylaminopyridine, picoline, lutidine, collidine, piperidine, dimethylpiperidine, N-methylmorpholine, N,N-dimethylaniline, quinoline, diazabicycloundecene, diazabicyclononene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, and 1,4-diazabicyclo[2.2.2]octane; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, and potassium t-butoxide. These may be used alone or in combination of two or more. Among these, organic bases are preferred, and among organic bases, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, and pyridine are more preferred, and triethylamine and pyridine are even more preferred. The amount of base used is preferably 0.1 mol or more, and preferably 0.5 mol or more, relative to 1 mol of the compound represented by general formula (II). There is no particular upper limit to the amount used, but from the viewpoint of economy, it is generally preferred to use a ratio of 10 mol or less, preferably 5 mol or less.

[0020] In the method for producing a phosphocholine compound of the present invention, the reaction can be carried out in the presence of a solvent to further promote the progress of the reaction. The solvent used is not particularly limited as long as it can dissolve or disperse the compound represented by general formula (I) and the compound represented by general formula (II). Specific examples include dichloromethane, chloroform, dimethyl sulfoxide, sulfolane, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, dimethylimidazolidinone, cyclohexanone, γ-butyrolactone, dihydrolevoglucosenone, monoglyme, and diglyme. These solvents may be used alone or in combination of two or more. Among these, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, and dihydrolevoglucosenone are preferred, with dimethyl sulfoxide and dimethylformamide being more preferred. Furthermore, among the above-mentioned organic bases, those that are liquid at the reaction temperature can also be used as the solvent. The amount of the solvent used is not particularly limited, but is usually 0.2 times by mass or more, preferably 0.5 times by mass or more, based on the total mass of the compound represented by general formula (I) and the compound represented by general formula (II). The upper limit of the amount used is not particularly limited, but from the viewpoint of economy, it is generally 10 times by mass or less, preferably 5 times by mass or less.

[0021] In the method for producing a phosphocholine compound of the present invention, the reaction temperature is generally 0 to 100° C., preferably 5 to 90° C., and more preferably 10 to 80° C., from the viewpoint of more efficiently proceeding the reaction. The reaction time is not particularly limited, but is generally 2 to 72 hours, preferably 4 to 60 hours, and more preferably 6 to 48 hours.

[0022] The phosphocholine compound of the present invention produced by the above-mentioned production method may be used for the intended purpose as it is, or may be purified by a purification method commonly used in the art, such as extraction, deacidification, washing with water, recrystallization, reprecipitation, cleaning, filtration, distillation, various column chromatography methods, etc.

[0023] <Method for Producing Phosphocholine Derivative> The phosphocholine compound of the present invention (a compound represented by the general formula (1)) can be reacted with a substrate compound having a hydroxyl group to produce a compound (phosphocholine derivative) in which a phosphocholine group has been introduced into the hydroxyl group of the substrate in a one-step reaction.

[0024] The substrate into which a phosphocholine group is introduced by the phosphocholine compound of the present invention may be any compound having a hydroxyl group, and is not particularly limited. Examples of compounds having a hydroxyl group that can serve as substrates are listed below, but the present invention is not limited to these. Examples of substrates that can be used include aliphatic monoalcohols, aliphatic diols, polyhydric alcohols, aromatic alcohols, phenolic compounds, mono- or dialkyl glyceryl ethers, mono- or diacylglycerols, sphingosines, ceramides, sterols, tocopherols, and sugars. These substrates may be used alone or in combination of two or more.

[0025] More specifically, the aliphatic monoalcohol includes saturated or unsaturated, straight-chain or branched monohydric alcohols or alicyclic monohydric alcohols having 1 to 32 carbon atoms, and further specifically, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, heneicosanol, and docosanol. , tricosanol, tetracosanol, isopropyl alcohol, isobutyl alcohol, isopentyl alcohol, isohexyl alcohol, isoheptyl alcohol, isooctyl alcohol, isononyl alcohol, isodecyl alcohol, isoundecyl alcohol, isododecyl alcohol, isotridecyl alcohol, isotetradecyl alcohol, isopentadecyl alcohol, isohexadecyl alcohol, isoheptadecyl alcohol, isostearyl alcohol, isononadecyl alcohol, isoeicosyl alcohol, isohene Eicosyl alcohol, isodocosyl alcohol, 2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 2-undecanol, 2-dodecanol, 2-tridecanol, 2-tetradecanol, 2-pentadecanol, 2-hexadecanol, 2-heptadecanol, 2-octadecanol, 2-nonadecanol, 2-eicosanol, 2-ethylhexanol, 2-butyloctanol, 2-hexyldecanol, 2-octyldodecanol, 2-decyltetradecanol ethanol, 2-dodecylhexadecanol, 2-tetradecyloctadecanol, 6-methyl-2-heptanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether,Saturated linear or branched monohydric alcohols such as triethylene glycol monopropyl ether and triethylene glycol monobutyl ether; 2-propen-1-ol, 2-methyl-2-propen-1-ol, 3-buten-1-ol, 2-buten-1-ol, 1-buten-3-ol, 2-methyl-3-buten-1-ol, 3-methyl-2-buten-1-ol, 3-methyl-3-buten-1-ol, 4-penten-1-ol, 1-penten-3-ol, 5-hexen-1-ol, 3-hexen-1-ol, and 1-hexen-3-ol , 6-hepten-1-ol, 1-hepten-3-ol, 7-octen-1-ol, 1-octen-3-ol, 8-nonen-1-ol, 1-nonen-3-ol, 9-decen-1-ol, 1-decen-3-ol, 10-undecen-1-ol, 1-undecen-3-ol, 11-dodecen-1-ol, 12-tridecen-1-ol, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxy 1-methylethyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate , 4-hydroxybutyl (meth)acrylate, 4-hydroxyphenyl (meth)acrylate, N-(hydroxymethyl) (meth)acrylamide, N-(2-hydroxyethyl) (meth)acrylamide, N-(2-hydroxypropyl) (meth)acrylamide, N-(4-hydroxyphenyl) (meth)acrylamide, 4-hydroxystyrene, palmitoleyl alcohol, oleyl alcohol, elaidyl alcohol, linoleyl alcohol, erucyl alcohol, brassidyl alcohol, geraniol, farnesol, nerol, citronellol Unsaturated linear or branched monohydric alcohols such as nerol; cyclohexanol, cyclohexanemethanol, cyclohexaneethanol, 4-isopropylcyclohexanol, 4-isopropylcyclohexanemethanol, 1-(4-isopropylcyclohexyl)ethanol, 4-tert-butylcyclohexanol, 4-tert-butylcyclohexanemethanol, hydroxypiperidine, 7-(beta-hydroxyethyl)theophylline, 5-norbornene-2-methanol, borneol, menthol, retinol, fenchyl alcohol,Alicyclic monohydric alcohols such as glycyrrhetinic acid are also included.

[0026] More specifically, the aliphatic diol includes saturated or unsaturated, straight-chain or branched dihydric alcohols or alicyclic dihydric alcohols having 2 to 32 carbon atoms, and further specifically, ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,4-butanediol, 1,3-butanediol, 1,2-butanediol, 1,5-pentanediol, 1,2-pentanediol, 2,2-dimethyl-1,3-propanediol, and 1,6-hexanediol. , 2,5-hexanediol, 1,2-hexanediol, 2-methyl-2,4-pentanediol, 3-methyl-1,5-pentanediol, 1,7-heptanediol, 1,2-heptanediol, 2,2-diethyl-1,3-propanediol, 1,8-octanediol, 1,2-octanediol, 2,2,4-trimethyl-1,5-pentanediol, 1,9-nonanediol, 1,2-nonanediol, 2-butyl-2-ethyl-1,3-propanediol, 2,4-diethyl-1,5-pentanediol, 1,10-decanediol, 1,2-decanediol, 1,12-dodecanediol, 1,2-dodecanediol, 1,14-tetradecanediol, 1,2-tetradecanediol, 1,16-hexadecanediol, 1,2-hexadecanediol, 1,18-octadecanediol, 1,2-octadecanediol, 1,12-octadecanediol, diethylene glycol, triethylene glycol, tetraethylene glycol saturated linear or branched dihydric alcohols such as ethylene glycol, polyethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol, polypropylene glycol, polytrimethylene ether glycol, and polytetramethylene ether glycol; unsaturated linear or branched dihydric alcohols such as 2-butene-1,4-diol, 3-hexene-2,5-diol, 4-octene-1,8-diol, and 9-octadecene-1,12-diol;Alicyclic dihydric alcohols such as 1,4-cyclohexanediol, 1,3-cyclohexanediol, 1,2-cyclohexanediol, 1,4-cyclohexanedimethanol, 1,3-cyclohexanedimethanol, 1,2-cyclohexanedimethanol, isosorbide, 2,3-norbornanedimethanol, 2,5-norbornanedimethanol, tricyclodecane dimethanol, 1,3-adamantanediol, 2,2-adamantanediol, 4,4'-isopropylidenedicyclohexanol, dimer diol, and hydrogenated bisphenol A are included;

[0027] More specifically, polyhydric alcohols include trihydric or higher aliphatic alcohols having 3 to 18 carbon atoms and polymers having three or more hydroxyl groups, and more specifically, trihydric or higher aliphatic alcohols such as glycerin, diglycerin, triglycerin, polyglycerin, erythritol, erythritan, sorbitol, sorbitan, xylitol, mannitol, maltitol, lactitol, trimethylolethane, trimethylolpropane, ditrimethylolpropane, pentaerythritol, and dipentaerythritol; poly 2-hydroxyethyl (meth)acrylate; poly 2-hydroxypropyl (meth)acrylate; Examples of the polymer include polymers having three or more hydroxyl groups and having a repeating unit such as poly(N-hydroxymethyl)(meth)acrylamide, poly(2-hydroxyethyl)(meth)acrylamide, poly(2-hydroxypropyl)(meth)acrylamide, poly(4-hydroxyphenyl)(meth)acrylamide, poly(4-hydroxyphenyl)(meth)acrylamide, poly(4-hydroxystyrene), and poly(vinyl alcohol).

[0028] More specifically, aromatic alcohols include compounds having an aromatic structure with 7 to 24 carbon atoms and having one or more hydroxyl groups other than a phenolic hydroxyl group, and further specific examples include benzyl alcohol, phenethyl alcohol, phenoxyethanol, ethylene glycol monobenzyl ether, diethylene glycol monobenzyl ether, triethylene glycol monobenzyl ether, 3-phenyl-1-propanol, cinnamyl alcohol, diphenylmethanol, diphenylethanol, diphenylpropanol, triphenylmethanol, triphenylethanol, and compounds in which hydrogen atoms on the aromatic rings of these compounds are substituted with one or more groups selected from a hydrocarbon group, an alkoxy group, a carboxyl group, a carbonyl group, a halogen group, an amino group, a nitro group, and a cyano group.

[0029] More specifically, the phenolic compound includes compounds having one or more phenolic hydroxyl groups having 6 to 30 carbon atoms, and further specifically includes phenol, dihydroxybenzene, trihydroxybenzene, hexahydroxybenzene, hydroxybenzyl alcohol, dihydroxybenzyl alcohol, hydroxyphenethyl alcohol, dihydroxyphenethyl alcohol, phenylphenol, diphenylphenol, triphenylphenol, hydroxynaphthalene, dihydroxynaphthalene, hydroxybiphenyl, dihydroxybiphenyl, hydroxyterphenyl, dihydroxyterphenyl, bisphenol A, hydroxypyridine, dihydroxypyridine, and compounds in which hydrogen atoms on the aromatic rings of these compounds are substituted with one or more groups selected from a hydrocarbon group, an alkoxy group, a carboxyl group, a carbonyl group, a halogen group, an amino group, a nitro group, and a cyano group; isopropylmethylphenol, salicylic acid, an alkyl salicylate, salicylic aldehyde, salicylic alcohol, Gallic acid, alkyl gallate, sinapyl alcohol, vanillyl alcohol, zingerone, shogaol, capsaicin, esculetin, scopoletin, umbelliferone, 4-methylumbelliferone, magnolol, magnolignan, pyridoxine, pyridoxal, ubiquinol, eugenol, arbutin, salicin, oryzanol, ferulic acid, caffeic acid, chlorogenic acid, rosmarinic acid, curcumin, chrysin, apiin, apigenin, luteonin, fisetin, kaempferol, quercetin Examples of polyphenol compounds include ellagic acid, catechin, epicatechin, epicatechin gallate, epigallocatechin gallate, theaflavin, cyanidin, anthocyanin, anthocyanidin, proanthocyanidin, procyanidin, and resveratrol.

[0030] More specifically, the mono- or di-alkyl glyceryl ether includes mono- or di-ethers of glycerin with a saturated or unsaturated, linear, branched or cyclic hydrocarbon group having 1 to 24 carbon atoms, and further specifically includes monomethyl glyceryl ether, monoethyl glyceryl ether, monopropyl glyceryl ether, monobutyl glyceryl ether, monopentyl glyceryl ether, monohexyl glyceryl ether, monoheptyl glyceryl ether, monooctyl glyceryl ether, monononyl glyceryl ether, monodecyl glyceryl ether, monoundecyl glyceryl ether, monododecyl glyceryl ether, monotetradecyl glyceryl ether, monohexadecyl glyceryl ether, monooctadecyl glyceryl ether, monoeicosyl glyceryl ether, monoisopropyl glyceryl ether, mono-2-ethylhexyl glyceryl ether, mono-2-hexyldecyl glyceryl ether, mono-2-octyldodecyl glyceryl ether, monoisostearyl glyceryl monoalkyl glyceryl ethers such as monooleyl glyceryl ether, monocyclohexyl glyceryl ether, and monomenthyl glyceryl ether; and dialkyl glyceryl ethers such as dimethyl glyceryl ether, diethyl glyceryl ether, dipropyl glyceryl ether, dibutyl glyceryl ether, dipentyl glyceryl ether, dihexyl glyceryl ether, diheptyl glyceryl ether, dioctyl glyceryl ether, dinonyl glyceryl ether, didecyl glyceryl ether, diundecyl glyceryl ether, didodecyl glyceryl ether, ditetradecyl glyceryl ether, dihexadecyl glyceryl ether, dioctadecyl glyceryl ether, dieicosyl glyceryl ether, diisopropyl glyceryl ether, di-2-ethylhexyl glyceryl ether, di-2-octyldodecyl glyceryl ether, diisostearyl glyceryl ether, dioleyl glyceryl ether, and dicyclohexyl glyceryl ether.

[0031] More specifically, the mono- or diacylglycerol includes mono- or diesters of glycerin with a fatty acid having a saturated or unsaturated, linear, branched, or cyclic hydrocarbon chain having 2 to 24 carbon atoms, and further specifically includes glyceryl monoacetate, glyceryl monobutyrate, glyceryl monovalerate, glyceryl monocaproate, glyceryl monoenanthate, glyceryl monocaprylate, glyceryl monopelargonate, glyceryl monocaprate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl monostearate, glyceryl monoeicosanoate, glyceryl monobehenate, glyceryl mono-2-ethylhexanoate, glyceryl mono-2-hexyldecanoate, glyceryl mono-2-octyldodecanoate, glyceryl monoisostearate, monopalmitoleate, glyceryl monoisostearate ... Examples thereof include monoacylglycerins such as glyceryl, glyceryl monooleate, glyceryl monolinoleate, and glyceryl monoerucate; and diacylglycerins such as glyceryl diacetate, glyceryl dibutyrate, glyceryl divalerate, glyceryl dicaproate, glyceryl dienanthate, glyceryl dicaprylate, glyceryl dipelargonate, glyceryl dicaprate, glyceryl dilaurate, glyceryl dimyristate, glyceryl dipalmitate, glyceryl distearate, glyceryl dieicosanoate, glyceryl dibehenate, glyceryl di-2-ethylhexanoate, glyceryl di-2-hexyldecanoate, glyceryl di-2-octyldodecanoate, glyceryl diisostearate, glyceryl dipalmitoleate, glyceryl dioleate, glyceryl dilinoleate, and glyceryl dierucate.

[0032] Sphingosines are a general term for compounds having a long-chain amino alcohol structure, also known as a sphingoid base, which forms the basic skeleton of sphingolipids distributed throughout the biological kingdom. More specifically, sphingosines include sphingosine, dihydrosphingosine, phytosphingosine, sphingadienine, and their N-methyl and N,N-dimethyl derivatives.

[0033] Ceramides are a type of sphingolipid distributed throughout the biological world, and are a general term for a group of compounds in which the sphingosines and fatty acids are bonded by an amide bond. More specific examples include ceramide 1, ceramide 2, ceramide 3, ceramide 4, ceramide 5, ceramide 6, and ceramide 7.

[0034] Sterols are a general term for compounds that are distributed throughout the biological world and have a hydroxyl group at the third carbon atom of a cyclopentanophenanthrene ring. More specifically, examples include animal-derived sterols such as cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol, and desmosterol; plant-derived sterols such as stigmasterol, sitosterol, campesterol, brassicasterol, and phytosterols, which are mixtures of these; and microbial-derived sterols such as ergosterol.

[0035] Tocopherols are a general term for compounds found in the biological world in which an isoprene side chain is bonded to a chroman ring having a phenolic hydroxyl group, and more specific examples include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.

[0036] The sugars include monosaccharides having a five- or six-membered ring structure distributed throughout the living world, as well as disaccharides and polysaccharides formed by combining these. More specifically, sugars include arabinose, xylose, lyxose, ribose, xylulose, ribulose, galactose, glucose, mannose, sorbose, tagatose, psicose, fructose, arabinose, glucosamine, N-acetylglucosamine, galactosamine, maltose, isomaltose, sophorose, cellobiose, trehalose, lactose, sucrose, lactulose, kestose, raffinose, maltotriose, melezitose, cyclodextrin, xylooligosaccharides, cellulose oligosaccharides, lacto-oligosaccharides, fructooligosaccharides, galactooligosaccharides, xanthan gum, locust bean gum, gellan gum, tamarind seaweed, and the like. Examples of such cellulose gums include gum arabic, galactomannan, glucomannan, starch, amylose, pullulan, dextrin, dextran, fructan, inulin, mannan, agar, carrageenan, chitin, chitosan, pectin, glucan, alginic acid, glycogen, cellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, cellulose nanofiber, guar gum, hydroxypropyl guar gum, hyaluronic acid, hydrolyzed hyaluronic acid, acetylated hyaluronic acid, Tremella fuciformis polysaccharide, chondroitin, chondroitin sulfate, heparin, and heparin-like substances, some of whose hydroxyl groups may be protected with protecting groups such as isopropylidene groups.

[0037] When reacting a phosphocholine compound with a substrate, the reaction ratio between the phosphocholine compound and the substrate may be adjusted appropriately depending on the type of substrate used. When the substrate is a compound having one hydroxyl group, there are methods in which the phosphocholine compound is used in excess relative to the substrate, and methods in which the substrate is used in excess relative to the phosphocholine compound. These methods may be selected appropriately taking into consideration the ease of purification after the reaction and production costs. When using an excess of the phosphocholine compound relative to the substrate, the phosphocholine compound may be reacted at a ratio of 1 to 10 moles, preferably 1.1 to 7.5 moles, and more preferably 1.2 to 5 moles, per mole of substrate. On the other hand, when using an excess of the substrate relative to the phosphocholine compound, the phosphocholine compound may be reacted at a ratio of 0.1 to 1 mole, preferably 0.13 to 0.9 moles, and more preferably 0.2 to 0.8 moles, per mole of substrate.

[0038] When the substrate is a compound having two or more hydroxyl groups, the reaction ratio between the phosphocholine compound and the substrate may be varied appropriately depending on the number of phosphocholine groups to be introduced into the substrate. When one phosphocholine group is to be introduced into the substrate, the substrate may be used in excess relative to the phosphocholine compound, and the phosphocholine compound may be reacted at a ratio of 0.1 to 1 mole, preferably 0.13 to 0.9 moles, and more preferably 0.2 to 0.8 moles per mole of substrate. When two or more phosphocholine groups are to be introduced into the substrate but fewer than the number of hydroxyl groups contained in the substrate, the phosphocholine compound may be reacted at a ratio of 0.8 to 1.2 moles × number of hydroxyl groups to be introduced, preferably 0.85 to 1.15 moles × number of hydroxyl groups to be introduced, more preferably 0.9 to 1.1 moles × number of hydroxyl groups to be introduced, per mole of substrate. When the same number of phosphocholine groups as the number of hydroxyl groups contained in the substrate are to be introduced into the substrate, the phosphocholine compound is reacted with 1 mole of substrate at a ratio of 1 to 10 moles × number of hydroxyl groups to be introduced, preferably 1.1 to 7.5 moles × number of hydroxyl groups to be introduced, more preferably 1.2 to 5 moles × number of hydroxyl groups to be introduced.

[0039] The reactivity of the phosphocholine compound of the present invention with hydroxyl groups increases in the order of tertiary hydroxyl groups < secondary hydroxyl groups < primary hydroxyl groups. Therefore, for example, when a substrate contains both primary and secondary hydroxyl groups, the phosphocholine group is basically preferentially introduced into the primary hydroxyl groups.

[0040] The reaction between the phosphocholine compound of the present invention and the substrate can be carried out in the absence or presence of a solvent. The solvent used is not particularly limited as long as it can dissolve or disperse the phosphocholine compound of the present invention and the substrate. Specific examples include organic solvents such as ethyl acetate, propyl acetate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide, sulfolane, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, dimethylimidazolidinone, cyclohexanone, γ-butyrolactone, dihydrolevoglucosenone, diethyl ether, tetrahydrofuran, dioxane, cyclopentyl methyl ether, monoglyme, and diglyme. Ionic liquids can also be used as solvents.Examples of ionic liquids include imidazolium-based cations such as 1-methyl-3-methylimidazolium, 1-ethyl-3-methylimidazolium, 1-propyl-3-methylimidazolium, 1-butyl-3-methylimidazolium, 1-hexyl-3-methylimidazolium, 1-decyl-3-methylimidazolium, 1-benzyl-3-methylimidazolium, 1-ethyl-2,3-dimethylimidazolium, and 1-butyl-2,3-dimethylimidazolium; 1-ethyl-1-methylpyrrolidinium; pyrrolidinium-based cations such as 1-ethyl-1-methylpyrrolidinium, 1-butyl-1-methylpyrrolidinium, 1-octyl-1-methylpyrrolidinium, and 1-(2-methoxyethyl)-1-methylpyrrolidinium; piperidinium-based cations such as 1-ethyl-1-methylpiperidinium, 1-propyl-1-methylpiperidinium, 1-butyl-1-methylpiperidinium, 1-octyl-1-methylpiperidinium, and 1-(2-methoxyethyl)-1-methylpiperidinium; 1-methylpyridinium, 1-ethyl-1-methylpiperidinium, 1-propyl-1-methylpiperidinium, 1-butyl-1-methylpiperidinium, 1-octyl-1-methylpiperidinium, and 1-(2-methoxyethyl)-1-methylpiperidinium; Examples of the ionic liquid include a combination of one selected from cationic compounds such as pyridinium cations such as 1-ethylpyridinium, 1-propylpyridinium, 1-butylpyridinium, 1-hexylpyridinium, 1-ethyl-3-methylpyridinium, 1-butyl-3-methylpyridinium, 1-ethyl-4-methylpyridinium, and 1-butyl-4-methylpyridinium; and phosphonium cations such as tetrabutylphosphonium, tetrahexylphosphonium, tetraoctylphosphonium, tributylmethylphosphonium, tributylhexylphosphonium, tributyloctylphosphonium, tributyldodecylphosphonium, tributylhexadecylphosphonium, tributyl(2-methoxyethyl)phosphonium, and trihexyltetradecylphosphonium, and one selected from anionic compounds such as chlorine, bromine, tetrafluoroborate, hexafluorophosphate, bis(trifluoromethanesulfonyl)imide, bis(fluorosulfonyl)imide, and alkylbenzenesulfonates. These may be used alone or in combination of two or more.The amount of solvent used is not particularly limited, but is usually 0.2 times or more, preferably 0.5 times or more, by mass relative to the total mass of the phosphocholine compound and the substrate. The upper limit of the amount used is not particularly limited, but from an economical standpoint, it is generally 10 times or less, preferably 5 times or less.

[0041] The reaction temperature between the phosphocholine compound of the present invention and the substrate is generally 60 to 240° C., preferably 80 to 220° C., and more preferably 90 to 200° C., from the viewpoint of more efficiently proceeding with the reaction. The reaction time is not particularly limited, but is generally 2 to 72 hours, preferably 4 to 60 hours, and more preferably 6 to 48 hours.

[0042] The above-described production method allows for the convenient production of a compound (phosphocholine derivative) in which a phosphocholine group is introduced into the hydroxyl group of a substrate. The phosphocholine derivative thus obtained can be purified by a purification method commonly used in the art, such as extraction, deacidification, washing with water, recrystallization, reprecipitation, cleaning, filtration, distillation, various column chromatography methods, etc.

[0043] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. １ H NMR measurements were performed using a JNM-AL300 manufactured by JEOL Datum Co., Ltd., and mass spectrometry was performed using a SCIEX QTRAP4500 manufactured by AB Sciex Corporation.

[0044] In the following examples, compounds synthesized or used in the present invention are represented as follows: When A is a compound represented by general formula (1) with structural formula (a), the compound is represented as (1-a). Similarly, when A is a compound represented by general formula (II) with structural formula (a), the compound is represented as (II-a).

[0045] Example 1 Synthesis of Phosphocholine Compound (1-c) (1) Under a nitrogen atmosphere, 15.7 g (0.09 mol) of phosphocholine (I) was placed in a reaction vessel, and 95 mL of dimethylformamide (DMF) was added as a solvent and stirred. Next, 55.6 g (0.34 mol) of 1,1'-carbonylbis-1H-imidazole (II-c) was added, followed by the dropwise addition of 35.1 g (0.35 mol) of triethylamine (TEA) as a base. After the dropwise addition, the mixture was reacted at 25°C for 24 hours, cooled to 5°C, and 11.8 g of ethanol was added dropwise and stirred for 30 minutes. The resulting reaction solution was concentrated under reduced pressure at 50°C, and then 230 mL of acetone was added to precipitate a solid. After cooling to 5°C, the solid was collected by suction filtration. The resulting solid was dried under reduced pressure to obtain the target compound (1-c) as a white powder. １ H NMR (300 MHz, solvent CD ３ OD): δ = 7.90 (s, 1H), 7.30 (d, J = 1.2Hz, 1H), 7.05 (m, 1H), 4.20-4.18 (m, 2H), 3.60-3.57 (m, 2H), 3.17 (s, 9H) Mass spectrometry (ESI): m / z = 234.3 [M + H] ＋

[0046] Example 2 Synthesis of Phosphocholine Compound (1-c) (2) 10.0 g (0.05 mol) of phosphocholine (I) was placed in a reaction vessel, and 20 g of dimethylformamide (DMF) was added as a solvent. The mixture was stirred at 40°C. Next, 26.6 g (0.16 mol) of 1,1'-carbonylbis-1H-imidazole (II-c) dissolved in 80.0 g of DMF was added dropwise. After the dropwise addition, the mixture was reacted at 40°C for 15 hours and then cooled to 20°C to precipitate a solid. The solid was recovered from the resulting suspension by suction filtration and washed by suspension in acetone. The resulting solid was dried under reduced pressure to obtain the target compound (1-c) as a white powder. １ H NMR (300 MHz, solvent CD ３ OD): δ = 7.90 (s, 1H), 7.30 (d, J = 1.2Hz, 1H), 7.05 (m, 1H), 4.20-4.18 (m, 2H), 3.60-3.57 (m, 2H), 3.17 (s, 9H) Mass spectrometry (ESI): m / z = 234.3 [M + H] ＋

[0047] Example 3 Synthesis of Phosphocholine Compound (1-c) (3) 10.0 g (0.05 mol) of phosphocholine (I) was placed in a reaction vessel, and 20 g of dimethyl sulfoxide (DMSO) was added as a solvent. The mixture was stirred at 40°C. Next, 26.6 g (0.16 mol) of 1,1'-carbonylbis-1H-imidazole (II-c) dissolved in 80.0 g of DMSO was added dropwise. After the dropwise addition, the mixture was reacted at 40°C for 15 hours and then cooled to 20°C to precipitate a solid. The solid was collected from the resulting suspension by suction filtration and washed by suspension in acetone. The resulting solid was dried under reduced pressure to obtain the target compound (1-c) as a white powder. １ H NMR (300 MHz, solvent CD ３ OD): δ = 7.90 (s, 1H), 7.30 (d, J = 1.2Hz, 1H), 7.05 (m, 1H), 4.20-4.18 (m, 2H), 3.60-3.57 (m, 2H), 3.17 (s, 9H) Mass spectrometry (ESI): m / z = 234.3 [M + H] ＋

[0048] Example 4 Synthesis of phosphocholine compound (1-d) Under a nitrogen atmosphere, 2.6 g (0.01 mol) of phosphocholine (I) was placed in a reaction vessel, and 15 mL of dimethylformamide (DMF) was added as a solvent and stirred. Next, 8.9 g (0.02 mol) of 3,3'-dimethyl-1,1'-carbonylbis-1H-imidazole methyl sulfate (II-d) was added, followed by the dropwise addition of 6.7 g (0.07 mol) of triethylamine (TEA) as a base. After the dropwise addition, the mixture was reacted at 25 ° C for 15 hours, cooled to 5 ° C, and 2.0 g of ethanol was added dropwise and stirred for 30 minutes. The resulting reaction solution was concentrated under reduced pressure at 50 ° C, and 50 mL of acetone was added to precipitate a solid. After cooling to 5 ° C, the solid was collected by suction filtration. The resulting solid was dried under reduced pressure, and the target compound (1-d) was obtained as a pale yellow wax. １H NMR (300MHz, solvent DMSO-d6): δ = 8.83 (s, 1H), 7.56 (m, 2H), 4.25 (m, 2H), 3.84 (s, 6H), 3.75 (s, 3H), 3.58-3.55 (m, 2H), 3.15 (s, 9H) Mass spectrometry (ESI): m / z=248.3 [M+H] ＋

[0049] Example 5 Synthesis of phosphocholine compound (1-m) Under a nitrogen atmosphere, 4.0 g (0.02 mol) of phosphocholine (I) was placed in a reaction vessel, and 20 mL of dimethylformamide (DMF) was added as a solvent and stirred. Next, 10.7 g (0.07 mol) of 1,1'-carbonyldi(1,2,4-triazole) (II-m) was added, followed by the dropwise addition of 6.7 g (0.07 mol) of triethylamine (TEA) as a base. After the dropwise addition, the mixture was reacted at 25°C for 36 hours, cooled to 5°C, and 2.0 g of ethanol was added dropwise and stirred for 30 minutes. The resulting reaction solution was concentrated under reduced pressure at 50°C, and 55 mL of acetone was added to precipitate a solid. After cooling to 5°C, the solid was collected by suction filtration. The resulting solid was dried under reduced pressure to obtain the target compound (1-m) as a pale yellow wax. １ H NMR (300MHz, solvent DMSO-d6): δ = 8.47 (s, 1H), 8.00 (s, 1H), 4.17-4.11 (m, 2H), 3.55-3.52 (m, 2H), 3.08 (s, 9H) Mass spectrometry (ESI): m / z = 235.3 [M+H] ＋

[0050] The following describes examples of synthesis of compounds (phosphocholine derivatives) in which a phosphocholine group is introduced into a hydroxyl group of a substrate using the phosphocholine compound of the present invention. The substrates used were 1-hexanol, p-nitrophenol, ceramide 2, cholesterol, and d-δ-tocopherol.

[0051] Example 6 Introduction of phosphocholine groups into 1-hexanol (1) 27.6 mg (0.12 mmol) of phosphocholine compound (1-c) and 36.3 mg (0.36 mmol) of 1-hexanol were placed in a reaction vessel and reacted with stirring for 17 hours at 150° C. The resulting reaction solution was purified by silica gel column chromatography (elution solvent: a mixture of chloroform / methanol / water) to obtain the target compound as a white powder. １ H NMR (300 MHz, solvent CDCl ３ : CD ３ OD=20:1): δ=4.24 (m, 2H), 3.86 (q, J=6.6Hz, 2H), 3.63 (t, J=4.6Hz, 2H), 3.24 (s, 9H), 1.66-1.57 (m, 2H), 1.30-1.28 (m, 6H), 0.88 (t, J=6.6Hz, 3H) Mass spectrometry (ESI): m / z=268.4 [M+H] ＋

[0052] Example 7 Introduction of phosphocholine group into 1-hexanol (2) The synthesis was carried out in the same manner as in Example 6, except that the phosphocholine compound (1-d) was used instead of the phosphocholine compound (1-c), to obtain the target compound. １ H NMR (300 MHz, solvent CDCl ３ : CD ３ OD=20:1): δ=4.24 (m, 2H), 3.86 (q, J=6.6Hz, 2H), 3.63 (t, J=4.6Hz, 2H), 3.24 (s, 9H), 1.66-1.57 (m, 2H), 1.30-1.28 (m, 6H), 0.88 (t, J=6.6Hz, 3H) Mass spectrometry (ESI): m / z=268.4 [M+H] ＋

[0053] Example 8 Introduction of phosphocholine group into 1-hexanol (3) The synthesis was carried out in the same manner as in Example 6, except that the phosphocholine compound (1-m) was used instead of the phosphocholine compound (1-c), to obtain the target compound. １ H NMR (300 MHz, solvent CDCl ３ : CD ３OD=20:1): δ=4.24 (m, 2H), 3.86 (q, J=6.6Hz, 2H), 3.63 (t, J=4.6Hz, 2H), 3.24 (s, 9H), 1.66-1.57 (m, 2H), 1.30-1.28 (m, 6H), 0.88 (t, J=6.6Hz, 3H) Mass spectrometry (ESI): m / z=268.4 [M+H] ＋

[0054] Example 9 Introduction of a phosphocholine group into p-nitrophenol A reaction vessel was charged with 55.6 mg (0.24 mmol) of the phosphocholine compound (1-c), 100.0 mg (0.72 mmol) of p-nitrophenol, and 1-butyl-3-methylimidazolium hexafluorophosphate ([C ４ dmim] [PF ６ 0.3 mL of chloroform / methanol / water was added, and the mixture was allowed to react for 18 hours with stirring at 120° C. The resulting reaction solution was purified by silica gel column chromatography (elution solvent: a mixture of chloroform / methanol / water) to obtain the target compound as a white powder. １ H NMR (300 MHz, solvent CDCl ３ : CD ３ OD = 3:1): δ = 8.21 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 4.34 (m, 2H), 3.64-3.61 (m, 2H), 3.22 (s, 9H) Mass spectrometry (ESI): m / z = 305.0 [M + H] ＋

[0055] Example 10 Introduction of a phosphocholine group into ceramide 2 39.7 mg (0.17 mmol) of phosphocholine compound (1-c) and 290.1 ​​mg (0.51 mmol) of ceramide 2 were placed in a reaction vessel and reacted with stirring for 16 hours at 120° C. The resulting reaction solution was purified by silica gel column chromatography (elution solvent: a mixture of chloroform / methanol / water) to obtain the target compound as a white powder. １ H NMR (300 MHz, solvent CDCl ３ : CD ３OD = 20:1): δ = 4.25-4.22 (m, 3H), 3.86-3.83 (m, 2H), 3.64-3.57 (m, 3H), 3.24 (s, 9 H), 2.19 (t, J = 7.5Hz, 2H), 1.60-1.53 ​​(m, 4H), 1.25 (m, 54H), 0.88 (t, J = 6.5Hz, 6H) Mass spectrometry (ESI): m / z=733.8 [M+H] ＋

[0056] Example 11 Introduction of phosphocholine groups into cholesterol A reaction vessel was charged with 51.2 mg (0.22 mmol) of the phosphocholine compound (1-c), 198.0 mg (0.51 mmol) of cholesterol, and 1-butyl-3-methylimidazolium hexafluorophosphate ([C ４ dmim] [PF ６ 0.5 mL of chloroform / methanol / water was added to the reaction solution, and the mixture was reacted for 17 hours with stirring at 150° C. The resulting reaction solution was purified by silica gel column chromatography (elution solvent: a mixture of chloroform / methanol / water) to obtain the target compound as a white powder. １ H NMR (300 MHz, solvent CDCl ３ : CD ３ OD = 1:1): δ = 5.37 (m, 1H), 4.24 (m, 2H), 4.01 (m, 1H), 3.65-3.60 (m, 2H), 3.22 (s, 9H), 2.40-2.36 ( m, 2H), 2.05-1.85 (m, 3H), 1.50-1.03 (m, 26H), 0.94-0.92 (m, 3H), 0.89-0.87 (m, 6H), 0.70 (s, 3H) Mass spectrometry (ESI): m / z=552.6 [M+H] ＋

[0057] Example 12 Introduction of a phosphocholine group into d-δ-tocopherol 50.0 mg (0.21 mmol) of phosphocholine compound (1-c) and 85 mg (0.21 mmol) of d-δ-tocopherol were placed in a reaction vessel and reacted with stirring for 20 hours at 100° C. The resulting reaction solution was purified by silica gel column chromatography (elution solvent: a mixture of chloroform / methanol / water) to obtain the target compound as a white powder. １H NMR (300 MHz, solvent CDCl ３ : CD ３ OD = 20:1): δ = 6.79 (d, J = 4.2Hz, 2H), 4.32 (m, 2H), 3.61 (m, 2H), 3.19 (s, 9H ), 2.10 (s, 3H), 1.77-1.68 (m, 2H), 1.57-1.07 (m, 26H), 0.88-0.83 (m, 12H) Mass spectrometry (ESI): m / z=568.3 [M+H] ＋

[0058] Using the phosphocholine compound of the present invention, the phosphocholine derivatives listed in Tables 1 to 3 were synthesized. The compounds having a hydroxyl group used as substrates were those listed in Tables 1 to 3. Table 1 shows an example in which phosphocholine compound (1-c) was used, Table 2 shows an example in which phosphocholine compound (1-d) was used, and Table 3 shows an example in which phosphocholine compound (1-m) was used.

[0059] <Synthesis Method> Approximately 50 mg of a phosphocholine compound and various substrates were charged into a reaction vessel in the reaction ratios shown in Tables 1 to 3, and the reaction was carried out in the absence or presence of a solvent at the reaction temperature / reaction time shown in Tables 1 to 3. The solvent used was 1-butyl-3-methylimidazolium hexafluorophosphate ([C ４ dmim] [PF ６ ]), or 1-(2-methoxyethyl)-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([Pyrr １，ＭＥ ] [FSA]) was used, and the amount of solvent used was 150 μL.

[0060] <Confirmation of the target product> Thin layer chromatography (TLC) analysis The reaction solution obtained by the above synthesis method was subjected to TLC analysis by the method described below. The TLC analysis confirmed that a spot of a new reaction product was formed and that this spot was positive with Dragendorff reagent (compounds having a choline structure develop color with Dragendorff reagent). This confirmed that the reaction product was a compound having a phosphocholine group (marked ○ in the TLC result column in the table).

[0061] TLC analysis method: Each reaction solution was diluted with a chloroform / methanol mixture and a fixed amount was charged onto a silica gel plate (Merck Silica Gel 60 F254). Next, depending on the polarity of the compound to be detected, chloroform / methanol / water = 60 / 30 / 5 (v / v / v) or 10 / 10 / 3 (v / v / v) was used as the developing solvent, and the plate was then dried, after which a phosphomolybdic acid solution was sprayed onto the plate as a color developer and the plate was heated to 150-200°C to detect spots. Spots were also detected in a similar manner using Dragendorff's reagent as a color developer.

[0062] Mass spectrometry (ESI) The reaction solution obtained by the above synthesis method was subjected to mass spectrometry (ESI) to determine the mass [M+H] of the target phosphocholine derivative predicted to be produced. ＋ It was confirmed that a peak with the same m / z value as that of the compound having a phosphocholine group, the production of which was confirmed by the TLC analysis, was observed. Therefore, the compound having a phosphocholine group, the production of which was confirmed by the TLC analysis, was identified as the target phosphocholine derivative (the mass spectrometry column in the table is marked with ○, and the observed m / z value is also listed).

[0063]

[0064]

[0065]

[0066] The structural formulae of the phosphocholine derivatives synthesized in Examples 13 to 52 in Tables 1 to 3 above are as follows:

[0067] Phosphocholine derivatives of Examples 13 and 45

[0068] Phosphocholine derivative of Example 14

[0069] Phosphocholine derivative of Example 15

[0070] Phosphocholine derivatives of Examples 16, 43, and 46

[0071] Phosphocholine derivative of Example 17

[0072] Phosphocholine derivative of Example 18

[0073] Phosphocholine derivative of Example 19

[0074] Phosphocholine derivative of Example 20

[0075] Phosphocholine derivative of Example 21

[0076] Phosphocholine derivative of Example 22

[0077] Phosphocholine derivative of Example 23

[0078] Phosphocholine derivative of Example 24

[0079] Phosphocholine derivative of Example 25

[0080] Phosphocholine derivative of Example 26

[0081] Phosphocholine derivative of Example 27

[0082] Phosphocholine derivative of Example 28

[0083] Phosphocholine derivative of Example 29

[0084] Phosphocholine derivative of Example 30

[0085] Phosphocholine derivative of Example 31

[0086] Phosphocholine derivative of Example 32

[0087] Phosphocholine derivative of Example 33

[0088] Phosphocholine derivative of Example 34

[0089] Phosphocholine derivative of Example 35

[0090] Phosphocholine derivative of Example 36

[0091] Phosphocholine derivative of Example 37

[0092] Phosphocholine derivative of Example 38

[0093] Phosphocholine derivatives of Examples 39 and 48

[0094] Phosphocholine derivatives of Examples 40 and 49

[0095] Phosphocholine derivatives of Examples 41 and 51

[0096] Phosphocholine derivative of Example 42

[0097] Phosphocholine derivatives of Examples 44 and 47

[0098] Phosphocholine derivative of Example 50

[0099] Phosphocholine derivative of Example 52

[0100] The results in Tables 1 to 3 confirm that by reacting the phosphocholine compound of the present invention with a substrate compound having a hydroxyl group, a compound (phosphocholine derivative) in which a phosphocholine group is introduced into the hydroxyl group of the substrate can be produced in a one-step reaction.

Claims

1. A nitrogen-containing heterocycle-containing phosphocholine compound represented by the following general formula (1): (wherein A is selected from the following structural formulas): (In the above structural formula, R ａ and R ｂ each independently represents an alkyl group, an alkenyl group, or an alkynyl group having 1 to 22 carbon atoms; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ each independently represents an alkyl group having 1 to 12 carbon atoms, and * indicates a bond.

2. The nitrogen-containing heterocycle-containing phosphocholine compound according to claim 1, wherein A in general formula (1) is selected from the following structural formulas: (In the above structural formula, R ａ and R ｂ each independently represents an alkyl group, an alkenyl group, or an alkynyl group having 1 to 22 carbon atoms; R １ , R ２ , R ３ , R ４ , R ６ , R ７ , R ８ and R ９ each independently represents an alkyl group having 1 to 12 carbon atoms, and * indicates a bond.

3. A method for producing a nitrogen-containing heterocycle-containing phosphocholine compound according to claim 1 or 2, characterized in that a compound represented by the following general formula (I) is reacted with a compound represented by the following general formula (II): (In the formula, A has the same meaning as A in general formula (1) described in claim 1 or 2.) 4. A method for producing a phosphocholine derivative, which comprises reacting the nitrogen-containing heterocycle-containing phosphocholine compound described in claim 1 or 2 with a compound having a hydroxyl group to produce a phosphocholine derivative in which a phosphocholine group has been introduced into the hydroxyl group of the compound having a hydroxyl group.

5. The manufacturing method according to claim 4, wherein the compound having a hydroxyl group is at least one selected from the group consisting of aliphatic monoalcohols, aliphatic diols, polyhydric alcohols, aromatic alcohols, phenolic compounds, mono- or di-alkyl glyceryl ethers, mono- or di-acyl glycerols, sphingosines, ceramides, sterols, tocopherols, and sugars.

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