Compound serving as intermediate for production of amino lipid or salt thereof, and amino lipid compound production method using same

Abstract

The present invention addresses the problem of providing: an amino lipid compound production method for producing an amino lipid with high purity; and an intermediate compound for use in the amino lipid compound production method. The present invention provides a compound represented by formula (1). In the formula, R1 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R2 represents a divalent hydrocarbon group having 1 to 12 carbon atoms; R3 represents a hydrocarbon group having 1 to 24 carbon atoms; R4 represents a hydrocarbon group having 1 to 7 carbon atoms; and R5 represents a divalent hydrocarbon group having 1 to 7 carbon atoms.

Description

Compound as an intermediate for the production of amino lipid or its salt, and method for producing amino lipid compound using the same

[0001] The present invention relates to a compound as an intermediate for the production of an amino lipid or a salt thereof, and a method for producing an amino lipid compound using the compound.

[0002] Nucleic acid drugs have a clear mechanism of action against diseases and few side effects, and are expected to be next-generation pharmaceuticals, and their development is actively underway. One known technique for delivering nucleic acids to cells is to administer nucleic acids encapsulated in liposomes or lipid particles. This technique uses lipids with substituents that become cationic at low pH, such as amino groups, and achieves nucleic acid delivery by imparting an appropriate charge to the particles.

[0003] Patent Documents 1, 2 and 3 describe the synthesis of synthetic intermediates for amino lipids using a reductive amination method.

[0004] International Publication No. WO2019 / 235635 International Publication No. WO2021 / 095876 International Publication No. WO2024 / 014430

[0005] An object of the present invention is to provide a method for producing an amino lipid compound for producing an amino lipid with high purity, as well as an intermediate compound used in the method for producing the amino lipid compound.

[0006] The present inventors have conducted extensive research to solve the above problems and have found that when deprotecting acetal in aqueous formic acid, the by-product ethanol reacts with the reactant formic acid to produce ethyl formate, and in the final step, this ethyl formate reacts with amine to become an impurity.The present inventors have conceived that by removing this ethyl formate in advance, the impurity content can be reduced and the purity of the amino lipid can be improved.The present invention has been completed based on the above findings.According to the present invention, the following inventions are provided.

[0007] <1> A compound represented by formula (1). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ４ represents a hydrocarbon group having 1 to 7 carbon atoms, and R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms. １ represents a hydrocarbon group having 3 to 8 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 5 carbon atoms; R ３ represents a hydrocarbon group having 12 to 24 carbon atoms; R ４ represents a hydrocarbon group having 1 to 3 carbon atoms or a benzyl group, and R ５ represents a divalent hydrocarbon group having 1 to 6 carbon atoms. or <4> A method for producing a compound represented by formula (4) or a salt thereof, comprising producing a compound represented by formula (2) from the compound represented by formula (1) according to <1>, and reacting the compound represented by formula (2) obtained above with a compound represented by formula (3) or a salt thereof: In the formula, R １ , R ２ , R ３ , and R ５ is as defined in claim 1, In the formula, R ６ represents a divalent hydrocarbon group having 2 to 4 carbon atoms, and R ７ and R ８ each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms; R ７ and R ８ The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by the formula (I) are each independently —OH, —COOH, —NR ９ R １０ , -OC(O)OR １１ , -C(O)O-R １２ , —OC(O)—R １３ , -O-R１４ , —C(O)NR １５ R １６ , -NR １７ C(O)R １８ , -N(R １９ ) S (O) ２ R ２０ , -N(R ２１ )C(O)N(R ２２ ) R ２３ , -N(R ２４ ) C(S)N(R ２５ ) R ２６ , -OC(O)N(R ２７ ) R ２８ , or -N(R ２９ )C(O)OR ３０ indicates R ９ and R １０ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , and R ３０ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８, R ２９ , and R ３０ The substituent on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, —OH, —COOH, or —NR ３１ R ３２ indicates R ３１ and R ３２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R ６ and R ７ , or R ７ and R ８ may be joined together to form a 4- to 7-membered ring, In the formula, R １ , R ２ , and R ３ is the same as defined in <1>, R ６ , R ７ and R ８ is defined as in formula (3), and R ９ and R １０ each independently represent a divalent hydrocarbon group having 2 to 7 carbon atoms. <5> The method according to <4>, comprising producing a compound represented by formula (2), concentrating the compound represented by formula (2), and then reacting the compound with a compound represented by formula (3) or a salt thereof. <6> A compound represented by formula (2). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms. １ represents a hydrocarbon group having 3 to 8 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 5 carbon atoms; R ３ represents a hydrocarbon group having 12 to 24 carbon atoms; R ５ represents a divalent hydrocarbon group having 1 to 6 carbon atoms. or The compound according to <6>, which is a compound represented by the formula:

[0008] According to the present invention, amino lipids can be produced with high purity.

[0009] The present invention will be described in detail below. In this specification, the symbol "to" indicates a range that includes the numerical values ​​before and after it as the minimum and maximum values, respectively.

[0010] <Intermediate for producing amino lipid or salt thereof> The intermediate of the first aspect of the present invention is a compound represented by formula (1). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ４ represents a hydrocarbon group having 1 to 7 carbon atoms, and R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms.

[0011] The intermediate of the second aspect of the present invention is a compound represented by formula (2). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms.

[0012] R １ R preferably represents a hydrocarbon group having 2 to 10 carbon atoms, more preferably a hydrocarbon group having 3 to 8 carbon atoms, even more preferably a hydrocarbon group having 5 to 8 carbon atoms, and particularly preferably a hydrocarbon group having 6 or 7 carbon atoms. ２ represents a divalent hydrocarbon group preferably having 2 to 10 carbon atoms, more preferably a divalent hydrocarbon group having 1 to 8 carbon atoms, even more preferably a divalent hydrocarbon group having 1 to 5 carbon atoms, and particularly preferably a hydrocarbon group having 5 carbon atoms. ３R preferably represents a hydrocarbon group having 4 to 24 carbon atoms, more preferably a hydrocarbon group having 8 to 24 carbon atoms, and even more preferably a hydrocarbon group having 12 to 24 carbon atoms. ４ R preferably represents a hydrocarbon group having 1 to 3 carbon atoms or a benzyl group. ５ represents a divalent hydrocarbon group preferably having 1 to 6 carbon atoms, more preferably a divalent hydrocarbon group having 1 to 4 carbon atoms, and even more preferably a divalent hydrocarbon group having 1 or 2 carbon atoms.

[0013] Specific examples of the compound represented by formula (1) are shown below, but the invention is not limited to these.

[0014] Specific examples of the compound represented by formula (2) are shown below, but the invention is not limited to these.

[0015] R １ The hydrocarbon group having 1 to 12 carbon atoms represented by is preferably an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or an alkynyl group having 2 to 12 carbon atoms, and more preferably an alkyl group having 1 to 12 carbon atoms. The hydrocarbon group having 1 to 12 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the hydrocarbon group having 1 to 12 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group.

[0016] R ２The divalent hydrocarbon group having 1 to 12 carbon atoms represented by is preferably an alkylene group having 1 to 12 carbon atoms or an alkenylene group having 2 to 12 carbon atoms. The divalent hydrocarbon group having 1 to 12 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the divalent hydrocarbon group having 1 to 12 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a nonamethylene group, a decamethylene group, an undecamethylene group, and a dodecamethylene group.

[0017] R ３ The hydrocarbon group having 1 to 24 carbon atoms represented by is preferably an alkyl group, an alkenyl group, or an alkynyl group. The alkyl group may be linear or branched, and may be chain-like or cyclic. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a trimethyldodecyl group (preferably a 3,7,11-trimethyldodecyl group), a tetradecyl group, a pentadecyl group, a hexadecyl group, a tetramethylhexadecyl group (preferably a 3,7,11,15-tetramethylhexadecyl group), a heptadecyl group, an octadecyl group, a 2-butylhexyl group, and a 2-butyloctyl group. , 1-pentylhexyl group, 2-pentylheptyl group, 3-pentyloctyl group, 1-hexylheptyl group, 1-hexylnonyl group, 2-hexyloctyl group, 2-hexyldecyl group, 3-hexylnonyl group, 1-heptyloctyl group, 2-heptylnonyl group, 2-heptylundecyl group, 3-heptyldecyl group, 1-octylnonyl group, 2-octyldecyl group, 2-octyldodecyl group, 3-octylundecyl group, 2-nonylundecyl group, 3-nonyldodecyl group, 2-decyldodecyl group, 2-decyltetradecyl group, 3-decyltridecyl group, 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl group, and the like.

[0018] The alkenyl group may be linear or branched, linear or cyclic. Specific examples include allyl, prenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl (preferably, (Z)-2-nonenyl or (E)-2-nonenyl), decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl (preferably, (Z)-tridec-8-enyl), tetradecenyl (preferably, tetradec-9-enyl), and pentadecenyl (preferably, (Z)-pentadecen-8-enyl). , a hexadecenyl group (preferably a (Z)-hexadec-9-enyl group), a hexadecadienyl group, a heptadecenyl group (preferably a (Z)-heptadeca-8-enyl group), a heptadecadienyl group (preferably a (8Z,11Z)-heptadeca-8,11-dienyl group), an octadecenyl group (preferably a (Z)-octadec-9-enyl group), an octadecadienyl group (preferably a (9Z,12Z)-octadeca-9,12-dienyl group), and the like.

[0019] The alkynyl group may be linear or branched, open-chain or cyclic, and specific examples thereof include a propargyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a nonynyl group, a decynyl group, an undecynyl group, a dodecynyl group, a tetradecynyl group, a pentadecynyl group, a hexadecynyl group, a heptadecynyl group, and an octadecynyl group.

[0020] Preferably, all of the above alkenyl groups have one or two double bonds, and preferably, all of the alkynyl groups have one or two triple bonds.

[0021] R ４The hydrocarbon group having 1 to 7 carbon atoms represented by is preferably an alkyl group having 1 to 7 carbon atoms, an alkenyl group having 2 to 7 carbon atoms, or an alkynyl group having 2 to 7 carbon atoms, and more preferably an alkyl group having 1 to 7 carbon atoms. The hydrocarbon group having 1 to 7 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the hydrocarbon group having 1 to 7 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, and a heptyl group.

[0022] R ５ The divalent hydrocarbon group having 1 to 7 carbon atoms represented by is preferably an alkylene group having 1 to 7 carbon atoms or an alkenylene group having 2 to 7 carbon atoms. The divalent hydrocarbon group having 1 to 7 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the divalent hydrocarbon group having 1 to 7 carbon atoms include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and a heptamethylene group.

[0023] <Method for producing an amino lipid compound represented by formula (4) or a salt thereof> The present invention relates to a method for producing a compound represented by formula (4) or a salt thereof, which comprises producing a compound represented by formula (2) from the compound represented by formula (1) described above, and reacting the compound represented by formula (2) obtained above with a compound represented by formula (3) or a salt thereof. In the formula, R １ , R ２ , R ３ , and R ５ is defined as in formula (1), In the formula, R ６ represents a divalent hydrocarbon group having 2 to 4 carbon atoms, and R ７ and R ８ each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms; R ７ and R ８ The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by the formula (I) are each independently —OH, —COOH, —NR ９ R１０ , -OC(O)OR １１ , -C(O)O-R １２ , —OC(O)—R １３ , -O-R １４ , —C(O)NR １５ R １６ , -NR １７ C(O)R １８ , -N(R １９ ) S (O) ２ R ２０ , -N(R ２１ )C(O)N(R ２２ ) R ２３ , -N(R ２４ ) C(S)N(R ２５ ) R ２６ , -OC(O)N(R ２７ ) R ２８ , or -N(R ２９ )C(O)OR ３０ indicates R ９ and R １０ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , and R ３０ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , and R ３０ The substituent on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, —OH, —COOH, or —NR ３１ R ３２ indicates R ３１ and R ３２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R ６ and R ７ , or R ７ and R ８ may be joined together to form a 4- to 7-membered ring, In the formula, R １ , R ２ , and R ３ is defined as in formula (1), and R ６ , R ７ and R ８ is defined as in formula (3), and R ９ and R １０ each independently represents a divalent hydrocarbon group having 2 to 7 carbon atoms.

[0024] Preferably, after producing the compound represented by formula (2), the compound represented by formula (2) is concentrated and then reacted with the compound represented by formula (3) or a salt thereof.

[0025] R ６ The divalent hydrocarbon group having 2 to 4 carbon atoms represented by is preferably an alkylene group or an alkenylene group, more preferably an alkylene group. Specific examples of the divalent hydrocarbon group having 2 to 4 carbon atoms include an ethylene group, a trimethylene group, and a tetramethylene group.

[0026] R ７ and R ８The hydrocarbon group having 2 to 4 carbon atoms represented by is preferably an alkyl group having 2 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, or an alkynyl group having 2 to 4 carbon atoms, and more preferably an alkyl group having 2 to 4 carbon atoms. The hydrocarbon group having 2 to 4 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the hydrocarbon group having 2 to 4 carbon atoms include an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a cyclobutyl group.

[0027] R ９ and R １０ The divalent hydrocarbon group having 2 to 7 carbon atoms represented by is preferably an alkylene group having 2 to 7 carbon atoms or an alkenylene group having 2 to 7 carbon atoms. The divalent hydrocarbon group having 2 to 7 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples of the divalent hydrocarbon group having 2 to 7 carbon atoms include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, and a heptamethylene group.

[0028] The compound represented by formula (3) may form a salt. The compound represented by formula (4) may form a salt. Examples of salts of basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid. Of the above-mentioned salts, preferred salts include pharmacologically acceptable salts.

[0029] <Production Method> The production method of the compound of the present invention will be described. The compound of the present invention can be produced by combining known methods, and can be produced, for example, according to the production method shown below.

[0030] [Production Method 1] A method for producing a compound of formula [1] from a compound of formula [2]. In the formula, R１ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and R 10 has the same meaning as above.

[0031] (1-1) The compound of formula [3] can be produced by reacting the compound of formula [2] in the presence of water and an acid, with or without a solvent. The acid used in this reaction can be an inorganic or organic acid. Organic acids are preferred, and specific examples include formic acid, acetic acid, trifluoroacetic acid, 4-toluenesulfonic acid, and methanesulfonic acid, which may be used in combination. A particularly preferred acid is formic acid. The amount of acid used can be 1 to 100 times (v / w), preferably 1 to 10 times (v / w), relative to the compound of formula [2]. The amount of water used can be 0.1 to 100 times (v / w), preferably 0.1 to 10 times (v / w), relative to the compound of formula [2]. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. The amount of the solvent used is not particularly limited, but may be 0 to 50 times (v / w) the amount of the compound of formula [2]. This reaction may be carried out at −30 to 150° C., preferably 0 to 100° C., for 5 minutes to 48 hours.

[0032] (1-2) The compound of formula [1] can be produced by reacting a compound of formula [3] with a compound of formula [4] in the presence of a reducing agent. Known examples of compounds of formula [4] include N,N-diethylethylenediamine and N,N-diethyl-1,3-diaminopropane. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used in combination. Preferred solvents include esters, with ethyl acetate being more preferred. The amount of solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [3]. Examples of reducing agents used in this reaction include sodium borohydride, sodium cyanoborohydride, pyridine borane, 2-picoline borane, and sodium triacetoxyborohydride, with sodium triacetoxyborohydride being more preferred. The amount of the reducing agent used may be 1 to 100 times, preferably 1 to 10 times, the molar amount of the compound of formula [3]. The amount of the compound of formula [4] used may be 0.1 to 1 times the molar amount of the compound of formula [3]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0033] [Production Method 2] A method for producing a compound of formula [2] from compounds of formula [5] and formula [6]. In the formula, R １ , R ２ , R ３ , R ４ and R ５ has the same meaning as above; X １means a leaving group." Examples of the leaving group include a chloro group, a fluoro group, a bromo group, a trichloromethoxy group, a 4-nitro-phenoxy group, a 2,4-dinitrophenoxy group, a 2,4,6-trichlorophenoxy group, a pentafluorophenoxy group, a 2,3,5,6-tetrafluorophenoxy group, an imidazolyl group, a triazolyl group, a 3,5-dioxo-4-methyl-1,2,4-oxadiazolidyl group, and an N-hydroxysuccinimidyl group.

[0034] The compound of formula [2] can be produced by reacting a compound of formula [5] with a compound of formula [6] in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used in combination. Preferred solvents include nitriles, with acetonitrile being more preferred. The amount of solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [5]. The base used in this reaction can be an inorganic base or an organic base. Specific examples include potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, lithium phosphate, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times, preferably 1 to 10 times, the molar amount of the compound of formula [5]. The amount of the compound of formula [6] used is not particularly limited, but may be 0.1 to 10 times the molar amount of the compound of formula [5]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0035] [Production Method 3] A method for producing a compound of the formula [5]. In the formula, R ４ and R ５ has the same meaning as above; X １ and X ２ means the same leaving group as above.

[0036] The compound of formula [5] can be produced by reacting a compound of formula [7] with a compound of formula [8] in the presence or absence of a base. Known examples of compounds of formula [7] include 2,2-diethoxyethanol. Known examples of compounds of formula [8] include 1,1'-carbonyldi(1,2,4-triazole), 1,1'-carbonyldiimidazole, 4-nitrophenyl chloroformate, triphosgene, and phosgene. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used in combination. Preferred solvents include ethers, with tetrahydrofuran being more preferred. The amount of solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [7]. Examples of the base used in this reaction include inorganic bases and organic bases. The base is preferably an organic base, and specific examples include triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times, preferably 1 to 10 times, the molar amount of the compound of formula [7]. The amount of the compound of formula [8] used is not particularly limited, but may be 1 to 10 times the molar amount of the compound of formula [7]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0037] [Production Method 4] A method for producing a compound of formula [6] from a compound of formula [9]. In the formula, R １ , R ２ and R ３ has the same meaning as above; X ３ means the same leaving group as above.

[0038] The compound of formula [6] can be produced by reacting a compound of formula [9] with a compound of formula

[10] in the presence or absence of a base and in the presence or absence of an additive. Examples of compounds of formula

[10] include 1-heptylamine and 1-hexylamine. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used in mixtures. Preferred solvents include mixed solvents of amides and esters, and a mixed solvent of dimethylformamide and ethyl acetate is more preferred. The amount of solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [9]. The base used in this reaction includes inorganic bases and organic bases. Specific examples of the base include potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, lithium phosphate, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine, with potassium carbonate being more preferred. The amount of the base used may be 1 to 50 times, preferably 1 to 10 times, the molar ratio of the compound of formula [9]. The amount of the compound of formula

[10] used is not particularly limited, but may be 1 to 10 times the molar ratio of the compound of formula [9]. Specific examples of additives used in this reaction include lithium iodide, sodium iodide, potassium iodide, benzyltriethylammonium iodide, and benzyltriethylammonium bromide. The amount of the additive used may be 0.1 to 10 times the molar ratio of the compound of formula [9]. This reaction may be carried out at a temperature of from -30 to 150°C, preferably from 0 to 100°C, for 5 minutes to 48 hours.

[0039] [Production Method 5] A method for producing a compound of the formula [9]. In the formula, R ２ , R ３ and X ３has the same meaning as above; X means a hydroxyl group or a leaving group; the leaving group has the same meaning as above.

[0040] The compound of formula [9] can be produced by reacting a compound of formula

[11] with a compound of formula

[12] in the presence or absence of an acid, in the presence or absence of a condensing agent or acid halide, and in the presence or absence of a base. Known examples of compounds of formula

[11] include 6-bromohexanoic acid and 5-bromovaleric acid. Known examples of compounds of formula

[12] include 2-butyl-1-octanol, 2-pentyl-1-heptanol, and 1-decanol. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used in combination. Preferred solvents include aromatic hydrocarbons and ethers, with toluene and tetrahydrofuran being more preferred. The amount of solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula

[11] . The acid used in this reaction includes inorganic and organic acids. The acid is preferably a sulfonic acid, and specific examples include sulfuric acid, 4-toluenesulfonic acid, and methanesulfonic acid. Condensing agents used in this reaction include, for example, carbodiimides such as N,N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; carbonyls such as carbonyldiimidazole; acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; and uroniums such as O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.Examples of acid halides used in this reaction include carboxylic acid halides such as acetyl chloride and trifluoroacetyl chloride; sulfonic acid halides such as methanesulfonyl chloride and tosyl chloride; and chloroformates such as ethyl chloroformate and isobutyl chloroformate. Examples of bases used in this reaction include inorganic and organic bases. Organic bases are preferred, and specific examples include triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine. The amount of base used may be 1 to 50 times, preferably 1 to 10 times, the molar ratio of the compound of formula

[11] . The amount of compound of formula

[12] used is not particularly limited, but may be 0.8 to 10 times (v / w) the amount of compound of formula

[11] . This reaction may be carried out at a temperature of from -30 to 150°C, preferably from 0 to 100°C, for 5 minutes to 48 hours.

[0041] <Use of the compound represented by formula (4) or its salt> The compound represented by formula (4) or its salt produced by the production method of the present invention can be used to prepare lipid particles. When preparing lipid particles, in addition to the compound represented by formula (4) or its salt, at least one lipid selected from the group consisting of sterols, neutral lipids, and lipids having nonionic hydrophilic polymer chains can be used. The lipid particles can further contain nucleic acids.

[0042] In the lipid particles, the amount of amino lipid blended is preferably 20 mol % to 80 mol %, more preferably 35 mol % to 70 mol %, and even more preferably 40 mol % to 65 mol %, relative to the total lipid amount.

[0043] Examples of sterols include, but are not limited to, cholesterol, phytosterols (sitosterol), stigmasterol, fucosterol, spinasterol, brassicasterol, ergosterol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, and cholesteryl-4'-hydroxybutyl ether. Of these, cholesterol is preferred. The amount of sterol blended is preferably 10 mol% to 60 mol%, more preferably 20 mol% to 55 mol%, and even more preferably 25 mol% to 50 mol%, based on the total lipid amount.

[0044] Neutral lipid is not particularly limited, but can be phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide etc., and preferably phosphatidylcholine and phosphatidylethanolamine.In addition, neutral lipid can be used alone or in combination with a plurality of different neutral lipids.In lipid particle, the amount of neutral lipid is preferably 3 mol% or more and 55 mol% or less with respect to the total amount of constituent lipid components.

[0045] Examples of nonionic hydrophilic polymers in lipids having nonionic hydrophilic polymer chains include, but are not limited to, nonionic vinyl polymers, nonionic polyamino acids, nonionic polyesters, nonionic polyethers, nonionic natural polymers, nonionic modified natural polymers, and block polymers or graft copolymers made up of two or more of these polymers as building blocks.Among these nonionic hydrophilic polymers, preferred are nonionic polyethers, nonionic polyesters, nonionic polyamino acids or nonionic synthetic polypeptides, more preferred are nonionic polyethers or nonionic polyesters, even more preferred are nonionic polyethers or nonionic monoalkoxy polyethers, and particularly preferred are polyethylene glycols (hereinafter, polyethylene glycols are also referred to as PEG).

[0046] Lipids having a nonionic hydrophilic polymer include, but are not limited to, PEG-modified phosphoethanolamine, diacylglycerol PEG derivatives, dialkylglycerol PEG derivatives, cholesterol PEG derivatives, and ceramide PEG derivatives. Among these, diacylglycerol PEG is preferred. The weight-average molecular weight of the PEG chain of the nonionic hydrophilic polymer derivative is preferably 500 to 5,000, more preferably 750 to 3,000. The nonionic hydrophilic polymer chain may be branched or may have a substituent such as a hydroxymethyl group.

[0047] In the lipid particles, the amount of lipid having a nonionic hydrophilic polymer chain is preferably 0.25 mol% to 12 mol%, more preferably 0.5 mol% to 6 mol%, and even more preferably 1 mol% to 3 mol%, relative to the total amount of lipid.

[0048] The lipid particles may contain nucleic acids. Examples of nucleic acids include plasmid DNA, nanoplasmid DNA, single-stranded DNA, double-stranded DNA, siRNA (small interfering RNA), miRNA (micro RNA), mRNA, antisense oligonucleotides, ribozymes, aptamers, dsRNA, saRNA, sgRNA, shRNA, tRNA, and cyclic RNA, and any of these may be contained. Furthermore, modified nucleic acids may be contained. RNA is particularly preferred as the nucleic acid, and RNA having 5 to 20,000 bases is preferred. In the lipid particles, the mass ratio of lipid to nucleic acid is preferably 2 to 1,000, more preferably 3 to 500, even more preferably 5 to 200, and particularly preferably 5 to 100.

[0049] The method for producing lipid particles is not limited, but can be produced by dissolving all or some of the oil-soluble components of the lipid particle in an organic solvent or the like to form an oil phase, dissolving the water-soluble components in water to form an aqueous phase, and mixing the oil phase and the aqueous phase. A micromixer may be used for mixing, or emulsification may be performed using an emulsifier such as a homogenizer, an ultrasonic emulsifier, a high-pressure injection emulsifier, or the like. Alternatively, lipid particles can be produced by preparing a dried mixture containing lipids by subjecting a lipid-containing solution to vacuum drying using an evaporator or the like or spray drying using a spray dryer, adding this mixture to an aqueous solvent, and further emulsifying using the above-mentioned emulsifier or the like.

[0050] An example of a method for producing lipid particles containing nucleic acid includes the following steps: (a) dissolving the components of lipid particles containing the compound represented by formula (4) or a salt thereof in an organic solvent to obtain an oil phase; (b) mixing the oil phase obtained in step (a) with an aqueous phase containing nucleic acid; (c) diluting the mixture containing the oil phase and aqueous phase obtained in step (b) to obtain a dispersion of nucleic acid-lipid particles; and (d) removing the organic solvent from the dispersion of nucleic acid-lipid particles obtained in step (c).

[0051] Lipid particles refer to particles composed of lipids, and include compositions having any structure selected from lipid aggregates in which lipids are aggregated, micelles, and liposomes, but the structure of the lipid particles is not limited to these as long as the composition contains lipids. Liposomes have a lipid bilayer structure and an aqueous phase inside, and include liposomes with a single bilayer membrane and multi-layered liposomes with multiple layers. Either type of liposome may be included in the present invention.

[0052] The morphology of lipid particles can be confirmed by electron microscope observation or X-ray structural analysis.For example, by using a cryo-transmission electron microscope (cryo-TEM) method, it can be confirmed whether the lipid particles have a lipid bilayer structure (lamellar structure) and an inner water layer, like liposomes, or whether the particles have a core with high electron density inside and a structure packed with lipids and other components.Small-angle X-ray scattering (SAXS) measurement can also be used to confirm whether the lipid particles have a lipid bilayer structure (lamellar structure).

[0053] As an example of the use of lipid particles, nucleic acid (e.g., genes) can be introduced into cells by introducing lipid particles containing nucleic acid into cells. Furthermore, when the lipid particles of the present invention contain nucleic acid having pharmaceutical uses, the lipid particles can be administered to a living body as a nucleic acid drug.

[0054] Lipid particles are highly useful as nucleic acid delivery carriers because they can retain nucleic acids at a high encapsulation rate. According to the nucleic acid delivery carrier of the present invention, for example, the obtained lipid particles can be mixed with nucleic acids and transfected in vitro, ex vivo, or in vivo to introduce nucleic acids into cells. The nucleic acid delivery carrier is also useful as a nucleic acid delivery carrier for nucleic acid medicines. That is, the lipid particles are useful as a composition for nucleic acid delivery in vitro, ex vivo, or in vivo.

[0055] The present invention will now be described with reference to examples, but the present invention is not limited to these examples.

[0056] Unless otherwise specified, purification by column chromatography was performed using an automatic purification system ISOLERA (Biotage), a medium-pressure preparative purification system Purif-espoir-2 (Shoko Science Co., Ltd.), or a medium-pressure liquid chromatograph YFLC W-prep 2XY (Yamazen Corporation). Unless otherwise specified, the carrier used in silica gel column chromatography was Chromatorex Q-Pack SI 50 (Fuji Silysia Chemical Ltd.), or Hi-Flash Column W001, W002, W003, W004, or W005 (Yamazen Corporation). NH silica gel was Chromatorex Q-Pack NH 60 (Fuji Silysia Chemical Ltd.). NMR spectra were measured using a Bruker AVNEO400 (Bruker) using tetramethylsilane as an internal standard, and all δ values ​​are expressed in ppm. MS spectra were measured using an ACQUITY SQD LC / MS System (manufactured by Waters).

[0057] [Example 1] (1)

[0058] A solution of 2,2-diethoxyethanol (5.0 g) in tetrahydrofuran (5 mL) was added to a solution of 1,1'-carbonyldi(1,2,4-triazole) (9.2 g) in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (100 mL) and 5% aqueous sodium bicarbonate (50 mL) were added, and the organic layer was separated. The resulting organic layer was washed with 5% aqueous sodium bicarbonate (50 mL) and saturated brine (30 mL), then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (7.52 g). １ H-NMR (CDCl ３ ) δ: 8.83 (1H, s), 8.08 (1H, s), 4.86 (1H, t, J = 5.3Hz), 4.48 (2H, d, J = 5.4Hz), 3.80-3.57 (4H, m), 1.22 (6H, t, J = 7.0Hz).

[0059] (2)

[0060] To a mixture of 2-pentyl-1-heptanol (15.0 g) and 6-bromohexanoic acid (18.1 g) in toluene (116 mL), p-toluenesulfonic acid monohydrate (1.50 g) was added and the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 10% aqueous sodium bicarbonate solution (105 mL) was added. The mixture was then transferred to a separatory funnel and washed with ethyl acetate (105 mL) and water (45 mL). The aqueous layer was discarded and washed with water (105 mL) and saturated brine (45 mL). The organic layer was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was removed by filtration. The filtrate was then distilled under reduced pressure at an external temperature of 40°C using an evaporator to obtain oily 2-pentylhexyl-6-bromohexanoic acid (28.7 g). １ H-NMR (CDCl ３ ) δ: 3.97 (2H, d, J = 5.8Hz), 3.40 (2H, t, J = 6.8Hz), 2.32 (2H, t, J = 7.4Hz), 1.91-1.84 (2H , m), 1.69-1.61 (3H, m), 1.51-1.44 (2H, m), 1.34-1.20 (16H, m), 0.88 (6H, t, J=6.9Hz).

[0061] (3)

[0062] A mixed solution of 2-pentylhexyl-6-bromohexanoic acid (27.0 g) in DMF (20 mL) and ethyl acetate (20 mL) was added dropwise over 20 minutes to a mixture of heptylamine (25.7 g), potassium carbonate (31.4 g), potassium iodide (37.0 g), DMF (80 mL), and ethyl acetate (80 mL), and the mixture was stirred for 2 hours. After adding ethyl acetate (100 mL) and water (160 mL), the mixture was transferred to a separatory funnel, the aqueous layer was discarded, and the organic layer was separated. The mixture was then washed with water (100 mL) and saturated brine (60 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane-ethyl acetate-methanol) to yield 2-pentylheptyl-6-(heptylamino)hexanoic acid (23.1 g) as a pale yellow oil. １ H-NMR (CDCl ３) δ: 3.96 (2H, d, J = 5.8Hz), 2.61-2.56 (4H, m), 2.31 (2H, t, J = 7.5Hz), 1.68-1.20 (34H, m), 0.88 (9H, m).

[0063] (4)

[0064] A mixture of 2-pentylheptyl-6-(heptylamino)hexanoic acid (15.0 g), triethylamine (7.4 g), acetonitrile (140 mL), and 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (10.4 g) was stirred at 50°C for 1 hour. After cooling to room temperature, ethyl acetate (150 mL) and 5% aqueous sodium bicarbonate (75 mL) were added, and the mixture was transferred to a separatory funnel and washed with ethyl acetate (20 mL). The aqueous layer was discarded and the mixture was washed with 5% aqueous sodium bicarbonate (75 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (normal silica, ethyl acetate-hexane) to give oily 2-pentylheptyl-6-(((2,2-diethoxyethoxy)carbonyl)(heptyl)amino)hexanoic acid (17.5 g). １ H-NMR (CDCl ３ ) δ: 4.69 (1H, t, J = 5.5Hz), 4.07 (2H, d, J = 5.6Hz), 3.96 (2H, t, J = 5.8Hz), 3.74-3.52 (4H , m), 3.28-3.12 (4H, m), 2.30 (2H, t, J=7.5Hz), 1.66-1.19 (39H, m), 0.90-0.86 (9H, m).

[0065] (5)

[0066] 2-pentylheptyl-6-(((2,2-diethoxyethoxy)carbonyl)(heptyl)amino)hexanoic acid (17.4 g), formic acid (35 mL), and water (8.5 mL) were added and stirred at 50 ° C. for 2 hours. After cooling to room temperature, ethyl acetate (250 mL) and a solution of sodium chloride (20 g) in water (75 mL) were added, transferred to a separatory funnel, and washed with ethyl acetate (10 mL). The aqueous layer was discarded and washed three times with 10% aqueous potassium carbonate (75 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain oily 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid (13.9 g) as a crude product. It was confirmed that the impurity content was reduced by removing the by-product ethyl formate during evaporation under reduced pressure, and the purity of the amino lipid could be improved. １ H-NMR (CDCl ３ ) δ: 9.61 (1H, s), 4.60 (2H, s), 3.96 (2H, d, J = 5.7Hz), 3.35-3.20 (4H, m), 2.30 (2H, t, J = 7.3Hz), 1.68-1.26 (33H, m), 0.89-0.85 (9H, m). MS m / z (M+H): 484.

[0067] (6)

[0068] To a solution of oily 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid (19.0 g) in ethyl acetate (190 mL) were added N,N-diethylethylenediamine (2.05 g) and sodium triacetoxyborohydride (25.0 g) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, 190 mL of 10% aqueous potassium carbonate solution was added dropwise under ice-cooling, the ice bath was removed, and the mixture was stirred for 5 minutes. The mixture was then transferred to a separatory funnel and washed with ethyl acetate (60 mL). The aqueous layer was discarded, and the mixture was washed with 10% aqueous potassium carbonate (190 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude A7. The resulting crude product was purified by silica gel column chromatography (normal silica, methanol-ethyl acetate-hexane), and the solvent was evaporated under reduced pressure. NH silica gel (15 g), hexane (60 mL), and ethyl acetate (15 mL) were added and stirred for 5 minutes. The mixture was then filtered through Celite and washed with a hexane / ethyl acetate solution (4:1, 300 mL). The solvent was evaporated under reduced pressure to obtain oily bis(2-pentylheptyl)-12-(2-(diethylamino)ethyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioate (16.4 g). The purity improved from 94.7% to 99.1% by removing the ethyl formate, demonstrating that the product can be synthesized with a higher purity than conventional methods. １ H-NMR (CDCl ３ ) δ: 4.10 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.25-3.08 (8H, m), 2.79 (4H, t, J = 6.4Hz), 2.68-2.64 (2H, m ), 2.54-2.48 (6H, m), 2.30 (4H, t, J = 7.5Hz), 1.70-1.18 (66H, m), 1.10 (6H, t, J = 7.1Hz), 0.90-0.86 (18H, m). MS m / z (M+H): 1052.

[0069] [Example 2] (3)

[0070] A solution of 2-pentylhexyl-6-bromohexanoic acid (1.0 g) in DMF (1 mL) and ethyl acetate (1 mL) was added dropwise to a mixture of hexylamine (0.84 g), potassium carbonate (1.20 g), potassium iodide (0.46 g), DMF (5 mL), and ethyl acetate (5 mL), and the mixture was stirred for 4 hours. After adding ethyl acetate (10 mL) and water (5 mL), the mixture was transferred to a separatory funnel, the aqueous layer was discarded, and the organic layer was separated. The mixture was then washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane-ethyl acetate-methanol) to yield 2-pentylheptyl-6-(hexylamino)hexanoic acid (873 mg) as a pale yellow oil. １ H-NMR (CDCl ３ ) δ: 3.96 (2H, d, J = 5.8Hz), 2.61-2.56 (4H, m), 2.31 (2H, t, J = 7.5Hz), 1.68-1.20 (32H, m), 0.88 (9H, m).

[0071] (4)

[0072] A mixture of 2-pentylheptyl-6-(hexylamino)hexanoic acid (4.50 g), triethylamine (2.14 g), acetonitrile (45 mL), and 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (2.91 g) was stirred at 50°C for 4 hours. After cooling to room temperature, ethyl acetate (80 mL) and 5% aqueous sodium bicarbonate (50 mL) were added, and the mixture was transferred to a separatory funnel and washed with ethyl acetate (20 mL). The aqueous layer was discarded, and the mixture was washed with 5% aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (normal silica, ethyl acetate-hexane) to give oily 2-pentylheptyl-6-(((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)hexanoic acid (5.93 g). １ H-NMR (CDCl ３) δ: 4.69 (1H, t, J = 5.5Hz), 4.07 (2H, d, J = 5.6Hz), 3.96 (2H, t, J = 5.8Hz), 3.74-3.52 (4H , m), 3.28-3.12 (4H, m), 2.30 (2H, t, J=7.5Hz), 1.66-1.19 (37H, m), 0.90-0.86 (9H, m).

[0073] (5)

[0074] 2-Pentylheptyl-6-(((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)hexanoic acid (5.71 g), formic acid (48 mL), and water (12 mL) were added and stirred at 50 ° C. for 2 hours. After cooling to room temperature, ethyl acetate (80 mL) and a solution of sodium chloride (20 g) in water (80 mL) were added, the mixture was transferred to a separatory funnel, and the mixture was washed with ethyl acetate (10 mL). The aqueous layer was discarded and the mixture was washed three times with 10% aqueous potassium carbonate (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain crude oily 2-pentylheptyl-6-(hexyl((2-oxoethoxy)carbonyl)amino)hexanoic acid (5.0 g). It was confirmed that the impurity content was reduced by removing the by-product ethyl formate during vacuum distillation, and the purity of the amino lipid could be improved. １ H-NMR (CDCl ３ ) δ: 9.61 (1H, s), 4.60 (2H, s), 3.96 (2H, d, J = 5.7Hz), 3.35-3.20 (4H, m), 2.30 (2H, t, J = 7.3Hz), 1.68-1.26 (31H, m), 0.89-0.85 (9H, m). MS m / z (M+H): 470.

[0075] (6)

[0076] To a solution of oily 2-pentylheptyl-6-(hexyl((2-oxoethoxy)carbonyl)amino)hexanoic acid (5.0 g) in ethyl acetate (50 mL) were added N,N-diethylethylenediamine (568 mg) and sodium triacetoxyborohydride (6.21 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 50 mL of 10% aqueous potassium carbonate solution was added dropwise under ice-cooling, the ice bath was removed, and the mixture was stirred for 5 minutes. The mixture was then transferred to a separatory funnel and washed with ethyl acetate (30 mL). The aqueous layer was discarded, and the mixture was washed with 10% aqueous potassium carbonate (50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude A7. The resulting crude product was purified by silica gel column chromatography (normal silica, methanol-ethyl acetate-hexane). The solvent was evaporated under reduced pressure to give oily bis(2-pentylheptyl)-12-(2-(diethylamino)ethyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioate (2.70 g) with high purity (purity 97.8%). １ H-NMR (CDCl ３ ) δ: 4.10 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.25-3.08 (8H, m), 2.79 (4H, t, J = 6.4Hz), 2.68-2.64 (2H, m ), 2.54-2.48 (6H, m), 2.30 (4H, t, J = 7.5Hz), 1.70-1.18 (62H, m), 1.10 (6H, t, J = 7.1Hz), 0.90-0.86 (18H, m). MS m / z (M+H): 1024.

[0077] [Example 3]

[0078] By using N,N-diethyl-1,3-propanediamine instead of N,N-diethylethylenediamine in Example 1 (6), a colorless oily substance, bis(2-pentylheptyl)-12-(3-(diethylamino)propyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioate, was obtained in high purity (purity 99.4%). １ H-NMR (CDCl ３) δ: 4.10 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.27-3.08 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.55 (2H, t, J = 7.3Hz), 2.50 (4H , q, J=7.2Hz), 2.41 (2H, t, J=7.5Hz), 2.30 (4H, t, J=7.5Hz), 1.70-1.16 (68H, m), 1.00 (6H, t, J=7.1Hz), 0.90-0.86 (18H, m). MS m / z (M+H): 1066.

[0079] Example 4 Compounds 35 to 40 were obtained in the same manner as in Example 1(4), except that in Example 1(2), a Br form shown in the table below was used instead of 6-bromohexanoic acid, and in Example 1(3), an amine shown in the table below was used instead of heptylamine.

[0080]

[0081]

[0082] Example 5 Compounds 41 to 46 were obtained by using the acetal starting material synthesized in Example 4 in the table below instead of using 2-pentylheptyl-6-(((2,2-diethoxyethoxy)carbonyl)(heptyl)amino)hexanoic acid in Example 1 (5).

[0083]

[0084] Example 6 Compounds 47 to 62 were obtained by using the amines in the table below instead of N,N-diethylethylenediamine in Example 1 (6).

[0085] Example 7 Compounds 63 to 68 were obtained by using 2-pentylheptyl-6-(octyl((2-oxoethoxy)carbonyl)amino)hexanoic acid instead of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid and an amine shown in the table below instead of N,N-diethylethylenediamine in Example 1 (6).

[0086]

[0087] [Example 8] (1)

[0088] To a solution of N-(2-aminoethyl)-N-methylethane-1,2-diamine (5.00 g) in dichloromethane (100 mL) was added a solution of di-tert-butyl dicarbonate (0.93 g) in dichloromethane (10 mL) under ice cooling, and the mixture was stirred for 30 minutes under ice cooling, then warmed to room temperature and stirred for 2 hours. Dichloromethane (100 mL) was added to the reaction solution, and the mixture was washed three times with saturated aqueous sodium chloride solution (25 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((2-aminoethyl)(methyl)amino)ethyl)carbamate.

[0089] (2)

[0090] Synthesis was performed in the same manner as in Example 1 (6), except that 2-pentylheptyl 6-(octyl((2-oxoethoxy)carbonyl)amino)hexanoic acid was used instead of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid and tert-butyl(2-((2-aminoethyl)(methyl)amino)ethyl)carbamate was used instead of N,N-diethylethylenediamine, to obtain a colorless oily substance, bis(2-pentylheptyl)12-(2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandieate. LC / MS rt(min): 1.68 MS(ESI,m / z): 1181.1 [M+H]+

[0091] (3)

[0092] Dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL) were added to bis(2-pentylheptyl) 12-(2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate (758 mg), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and ethyl acetate (30 mL) was added. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude bis(2-pentylheptyl) 12-(2-((2-aminoethyl)(methyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt(min): 1.61 MS(ESI,m / z): 1081.2 [M+H] +

[0093] (4)

[0094] To a dichloromethane solution (5.0 mL) of bis(2-pentylheptyl) 12-(2-((2-aminoethyl)(methyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandieate (200 mg) was added methyl isothiocyanate (15 mg) under ice-cooling, and the mixture was warmed to room temperature and stirred for 2 hours. To the reaction mixture under ice-cooling, dichloromethane (5 mL) was added, and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added dropwise. The mixture was then washed twice with saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and with saturated aqueous sodium chloride solution (5.0 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (normal silica, methanol-ethyl acetate-hexane) to obtain oily bis(2-pentylheptyl) 12-(2-(methyl(2-(3-methylthioureido)ethyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt(min): 1.65 MS(ESI,m / z): 1154.2 [M+H] +

[0095] [Example 9]

[0096] The synthesis was carried out in the same manner as in Example 8 (4), except that methanesulfonyl chloride and triethylamine were used instead of methyl isothiocyanate, to obtain a colorless oily substance, bis(2-pentylheptyl) 12-(2-(methyl(2-methylsulfonamido)ethyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt (min): 1.65 MS (ESI, m / z): 1159.1 [M+H] +

[0097] [Example 10] (1)

[0098] 3-Methoxy-4-(methylamino)cyclobut-3-ene-1,2-dione was obtained by the method described in WO2022 / 204380.

[0099] (2)

[0100] To a solution of the crude bis(2-pentylheptyl) 12-(2-((2-aminoethyl)(methyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate (200 mg) obtained in Example 8(3) in ethanol (5.0 mL) was added 3-methoxy-4-(methylamino)cyclobut-3-ene-1,2-dione, and the mixture was stirred at 50°C for 10 hours. The mixture was returned to room temperature, and ethyl acetate (10.0 mL) was added. The mixture was washed twice with saturated aqueous sodium hydrogen carbonate solution (10.0 mL) and then with saturated brine (10.0 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (normal silica, methanol-ethyl acetate-hexane) to obtain a white viscous solid, bis(2-pentylheptyl) 12-(2-(methyl(2-((2-(methylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)ethyl)amino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt(min): 1.69 MS(ESI,m / z): 1190.2 [M+H] +

[0101] [Example 11]

[0102] The synthesis was carried out in the same manner as in the synthesis of Compound 16, except that N-(3-aminopropyl)-N-methylpropane-1,3-diamine was used instead of N-(2-aminoethyl)-N-methylethane-1,2-diamine in Example 8 (1), to obtain a white viscous solid, bis(2-pentylheptyl)12-(3-(methyl(3-((2-(methylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)propyl)amino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt(min): 1.73 MS(ESI,m / z): 1218.2 [M+H] +

[0103] [Example 12]

[0104] Synthesis was performed in the same manner as in Example 9, except that N-(3-aminopropyl)-N-methylpropane-1,3-diamine was used instead of N-(2-aminoethyl)-N-methylethane-1,2-diamine in Example 8 (1), to obtain a colorless oily substance, bis(2-pentylheptyl)12-(3-(methyl(3-methylsulfonamido)propyl)amino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediaate. LC / MS rt(min): 1.61 MS(ESI,m / z): 1187.2 [M+H] +

[0105] [Example 13]

[0106] Synthesis was performed in the same manner as in Example 8, except that N-(3-aminopropyl)-N-methylpropane-1,3-diamine was used instead of N-(2-aminoethyl)-N-methylethane-1,2-diamine in Example 8 (1), to obtain a colorless oily substance, bis(2-pentylheptyl)12-(3-(methyl(3-(3-methylthioureido)propyl)amino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt(min): 1.73 MS(ESI,m / z): 1182.2 [M+H] +

[0107] [Example 14]

[0108] (1) 3-Hydroxyazetidine hydrochloride (1.42 g) was desalted using an ion exchange resin (Diaion SA10A (Mitsubishi Chemical), regenerated to the OH form), and the solvent was replaced with DMF (10 mL). To this was added tert-butyl (2-bromoethyl)carbamate (1.12 g) and potassium carbonate (2.0 g), and the mixture was stirred at 80°C for 60 minutes. The reaction mixture was separated using ethyl acetate / 1% hydrochloric acid, and the resulting aqueous layer was made basic with potassium carbonate (5 g) and then extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give tert-butyl (2-(3-hydroxyazetidin-1-yl)ethyl)carbamate (854 mg) as a colorless oil. LC / MS rt (min): 0.53 MS (ESI, m / z): 217.3 [M+H] +

[0109] (2) Trifluoroacetic acid (3 mL) was added to tert-butyl (2-(3-hydroxyazetidin-1-yl)ethyl)carbamate (480 mg) and stirred at room temperature for 30 minutes. Trifluoroacetic acid was removed by distillation under reduced pressure, and the resulting residue was desalted using an ion exchange resin (Diaion SA10A (Mitsubishi Chemical), regenerated to OH form) and azeotropically dehydrated with ethanol to give 1-(2-aminoethyl)-azetidin-3-ol (205 mg). LC / MS rt (min): 0.22 MS (ESI, m / z): 173.3 [M+H] +

[0110] (3) The synthesis was carried out in the same manner as in Example 1 (6), except that 2-pentylheptyl 6-(octyl((2-oxoethoxy)carbonyl)amino)hexanoic acid was used instead of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid, and 1-(2-aminoethyl)-azetidin-3-ol was used instead of N,N-diethylethylenediamine, to obtain a colorless oily substance, bis(2-pentylheptyl)12-(2-(3-hydroxyazetidin-1-yl)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt (min): 1.65 MS (ESI, m / z): 1094.15 [M+H] +

[0111] [Example 15]

[0112] (1) To a solution of tert-butyl (2-bromoethyl)carbamate (1.12 g) and potassium carbonate (2.0 g) in acetonitrile (10 mL), pyrrolidin-3-ol (1.3 mL) was added and stirred at 80 °C for 60 minutes. The reaction mixture was separated with ethyl acetate / 1% hydrochloric acid, and the resulting aqueous layer was made basic with potassium carbonate (5 g) and then extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the resulting residue was purified by NH silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (2-(3-hydroxypyrrolidin-1-yl)ethyl)carbamate (1.05 g) as a colorless oil. LC / MS rt (min): 0.54 MS (ESI, m / z): 231.3 [M+H] +

[0113] (2) Trifluoroacetic acid (10 mL) was added to tert-butyl (2-(3-hydroxypyrrolidin-1-yl)ethyl)carbamate (850 mg) and stirred at room temperature for 30 minutes. Trifluoroacetic acid was distilled off under reduced pressure, and the resulting residue was desalted using an ion exchange resin (Diaion SA10A (Mitsubishi Chemical), regenerated to OH form) and azeotropically dehydrated with ethanol to give 1-(2-aminoethyl)pyrrolidin-3-ol (643 mg). LC / MS rt (min): 0.22 MS (ESI, m / z): 131.3 [M+H] +

[0114] (3) In Example 14 (3), 1-(2-aminoethyl)pyrrolidin-3-ol was used instead of 1-(2-aminoethyl)azetidin-3-ol to obtain a colorless oily substance, bis(2-pentylheptyl)12-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandiate. LC / MS rt (min): 1.73, 1.94 MS (ESI, m / z): 1154.15 [M+H] +

[0115] [Example 16]

[0116] (1) To a solution of tert-butyl (2-bromoethyl)carbamate (A) (1.12 g) and potassium carbonate (2.0 g) in dimethylformamide (10 mL), 4-(ethylamino)butan-1-ol (II) (1.3 mL) was added and stirred at 80 °C for 30 minutes. The reaction mixture was separated with ethyl acetate / 1% hydrochloric acid, and the resulting aqueous layer was made basic with potassium carbonate (5 g) and then extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated to give tert-butyl (2-(ethyl(4-hydroxybutyl)amino)ethyl)carbamate (IIA) (1.08 g) as a colorless oil. LC / MS rt (min): 0.63 MS (ESI, m / z): 261.3 [M+H] +

[0117] (2) Trifluoroacetic acid (5 mL) was added to tert-butyl (2-(ethyl(4-hydroxybutyl)amino)ethyl)carbamate (IIA) (650 mg) and stirred at room temperature for 30 minutes. Trifluoroacetic acid was distilled off under reduced pressure, and the resulting residue was desalted using an ion exchange resin (Diaion SA10A (Mitsubishi Chemical), regenerated to OH form) and azeotropically dehydrated with ethanol to obtain 4-((2-aminoethyl)(ethyl)amino)butan-1-ol (IIA-NH). LC / MS rt (min): 0.19 MS (ESI, m / z): 161.2 [M+H] +

[0118] (3) Using 2-pentylheptyl 6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoate (0.50 g) and 4-((2-aminoethyl)(ethyl)amino)butan-1-ol (IIA-NH) (93 mg), bis(2-pentylheptyl) 12-(2-(ethyl(4-hydroxybutyl)amino)ethyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioate (375 mg) was obtained in the same manner as in Synthesis Example 31. LC / MS rt (min): 1.43 MS (ESI, m / z): 1097.2 [M+H] +

[0119] Example 17 In the same manner as in Example 16(1) to (3), tert-butyl (2-((4-hydroxybutyl)(methyl)amino)ethyl)carbamate (IA), tert-butyl (3-((4-hydroxybutyl)(methyl)amino)propyl)carbamate (IB), tert-butyl (2-(ethyl(4-hydroxybutyl)amino)ethyl)carbamate (IIA), and tert-butyl (2-bromoethyl)carbamate (A) and tert-butyl (3-bromopropyl)carbamate (B) were used to prepare tert-butyl (2-((4-hydroxybutyl)(methyl)amino)ethyl)carbamate (IA), tert-butyl (3-((4-hydroxybutyl)(methyl)amino)propyl)carbamate (IB), and tert-butyl (2-(ethyl(4-hydroxybutyl)amino)ethyl)carbamate (IIA). tert-butyl (3-(ethyl(4-hydroxybutyl)amino)propyl)carbamate (IIB), tert-butyl (2-((3-hydroxypropyl)(methyl)amino)ethyl)carbamate (IIIA), tert-butyl (3-((3-hydroxypropyl)(methyl)amino)propyl)carbamate (IIIB), tert-butyl (2-(ethyl(3-hydroxypropyl)amino)ethyl)carbamate (IVA), tert-butyl (3-(ethyl(3-hydroxypropyl)amino)propyl)carbamate (IVB), tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)carbamate (VA), tert-butyl (3-((2-hydroxyethyl)(methyl)amino)propyl)carbamate (VB), tert-butyl (2-(ethyl(2-hydroxyethyl)amino)ethyl)carbamate (VIA), and tert-butyl (3-(ethyl(2-hydroxyethyl)amino)propyl)carbamate (VIB), and then deprotection of the BOC group gave 4-((2-aminoethyl)(methyl)amino)butan-1-ol (IA-NH2), 4-((3-aminopropyl)(methyl)amino)butan-1-ol (IB-NH2),4-((2-aminoethyl)(ethyl)amino)butan-1-ol (IIA-NH2), 4-((3-aminopropyl)(ethyl)amino)butan-1-ol (IIB-NH2), 3-((2-aminoethyl)(methyl)amino)propan-1-ol (IIIA-NH2), 3-((3-aminopropyl)(methyl)amino)propan-1-ol (IIIB-NH2), 3-((2-aminoethyl)(ethyl)amino)propan-1-ol (IVA-NH2), 3-((3-aminopropyl)(ethyl)amino)propan-1-ol (IVB-NH2), 2-((2-aminoethyl)(methyl)amino)ethan-1-ol (VA-NH2), 2-((3-aminopropyl)(methyl)amino)ethan-1-ol (VB-NH2), 2-((2-aminoethyl)(ethyl)amino)ethan-1-ol (VIA-NH2) and 2-((3-aminopropyl)(ethyl)amino)ethan-1-ol (VIB-NH2) were synthesized (Table 6). Using these obtained amines and 2-pentylheptyl 6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoate or 2-pentyl 6-(octyl((2-oxoethoxy)carbonyl)amino)hexanoate, compounds (Compounds 69 to 92) were synthesized in the same manner as in Example 16 (Table 7).

[0120]

[0121]

[0122] Example 18 Compounds 93 and 94 were obtained by using 2-pentylheptyl-6-(nonyl((2-oxoethoxy)carbonyl)amino)hexanoic acid in place of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid and an amine in the table below in place of N,N-diethylethylenediamine in Example 1 (6).

[0123]

[0124] Example 19 Compounds 95 and 96 were obtained by using 2-pentylheptyl 6-(decyl((2-oxoethoxy)carbonyl)amino)hexanoic acid in place of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid and an amine in the table below in place of N,N-diethylethylenediamine in Example 1 (6).

[0125]

[0126] Example 20 Compounds 97 and 98 were obtained by using 2-(((3-oxo-3-((2-pentylheptyl)oxy)propyl)(pentyl)carbamoyl)oxy)acetic acid in place of 2-pentylheptyl-6-(heptyl((2-oxoethoxy)carbonyl)amino)hexanoic acid and an amine in the table below in place of N,N-diethylethylenediamine in Example 1 (6).

[0127]

[0128] Example 21 Compounds 99 to 100 were obtained by using the amines in the table below in place of 2-pentylheptyl 3-(hexyl((2-oxoethoxy)carbonyl)amino)propanoate and N,N-diethylethylenediamine in Example 1 (6).

[0129]

[0130] Example 22 Compounds 101 and 102 were obtained by using an amine shown in the following table instead of N,N-diethylethylenediamine for 2-pentylheptyl 3-(heptyl((2-oxoethoxy)carbonyl)amino)propanoate in Example 1 (6).

[0131]

Claims

1. A compound represented by formula (1). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ４ represents a hydrocarbon group having 1 to 7 carbon atoms, and R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms.

2. R １ represents a hydrocarbon group having 3 to 8 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 5 carbon atoms; R ３ represents a hydrocarbon group having 12 to 24 carbon atoms; R ４ represents a hydrocarbon group having 1 to 3 carbon atoms or a benzyl group, and R ５ The compound according to claim 1 , wherein represents a divalent hydrocarbon group having 1 to 6 carbon atoms.

3. or The compound according to claim 1, which is a compound represented by the formula:

4. A method for producing a compound represented by formula (4) or a salt thereof, comprising producing a compound represented by formula (2) from a compound represented by formula (1) according to claim 1, and reacting the compound represented by formula (2) obtained above with a compound represented by formula (3) or a salt thereof: In the formula, R １ , R ２ , R ３ , and R ５ is as defined in claim 1, In the formula, R ６ represents a divalent hydrocarbon group having 2 to 4 carbon atoms, and R ７ and R ８ each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms; R ７ and R ８ The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by the formula (I) are each independently —OH, —COOH, —NR ９ R １０ , -OC(O)OR １１ , -C(O)O-R １２ , —OC(O)—R １３ , -O-R １４ , —C(O)NR １５ R １６ , -NR １７ C(O)R １８ , -N(R １９ ) S (O) ２ R ２０ , -N(R ２１ )C(O)N(R ２２ ) R ２３ , -N(R ２４ ) C(S)N(R ２５ ) R ２６ , -OC(O)N(R ２７ ) R ２８ , or -N(R ２９ )C(O)OR ３０ indicates R ９ and R １０ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , and R ３０ each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms; R １１ , R １２ , R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ , R ２８ , R ２９ , and R ３０ The substituent on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, —OH, —COOH, or —NR ３１ R ３２ indicates R ３１ and R ３２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms; R ６ and R ７ , or R ７ and R ８ may be joined together to form a 4- to 7-membered ring, In the formula, R １ , R ２ , and R ３ has the same meaning as defined in claim 1, and R ６ , R ７ and R ８ is defined as in formula (3), and R ９ and R １０ each independently represents a divalent hydrocarbon group having 2 to 7 carbon atoms.

5. The method according to claim 4, wherein after producing the compound represented by formula (2), the compound represented by formula (2) is concentrated and then reacted with the compound represented by formula (3) or a salt thereof.

6. A compound represented by formula (2). In the formula, R １ represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 12 carbon atoms, and R ３ represents a hydrocarbon group having 1 to 24 carbon atoms, R ５ represents a divalent hydrocarbon group having 1 to 7 carbon atoms.

7. R １ represents a hydrocarbon group having 3 to 8 carbon atoms; R ２ represents a divalent hydrocarbon group having 1 to 5 carbon atoms; R ３ represents a hydrocarbon group having 12 to 24 carbon atoms; R ５ The compound according to claim 6, wherein represents a divalent hydrocarbon group having 1 to 6 carbon atoms.

8. or The compound according to claim 6, which is a compound represented by the formula:

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