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

Abstract

The present invention addresses the problem of providing: a method for producing an amino lipid compound with which the yield in a carbonation reaction is increased; and an intermediate compound used in the method for producing an amino lipid compound. According to the present invention, a compound represented by formula [1] or a salt thereof can be provided. In the formula, R1 represents a hydrogen atom or a hydrocarbon group having 1-12 carbon atoms, R2 represents a divalent hydrocarbon group having 2-12 carbon atoms, and R3 represents a hydrocarbon group having 6-22 carbon atoms. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound which is an intermediate for producing an amino lipid or a salt thereof, and a method for producing an amino lipid compound using the compound. Background Art

[0002] Nucleic acid drugs have a clear mechanism of action on diseases and few side effects. They are expected to be the next generation of pharmaceuticals, and the development of nucleic acid drugs is being actively carried out. As one of the technologies for delivering nucleic acids to cells, there is a method of administering nucleic acids by including nucleic acids in liposomes or lipid particles. In this technology, lipids having substituents that become cationic at low pH such as amino groups are used as lipids, and nucleic acid delivery is achieved by giving appropriate charges to particles.

[0003] As a compound contained in lipid particles, amino lipids synthesized by condensation of an aminophenyl carbonate intermediate and an alcohol are described in Patent Document 1. Also, amino lipids synthesized by condensation of a 1-imidazole carboxylate intermediate and an alcohol are described in Patent Document 2.

[0004] On the other hand, Patent Document 3 describes the use of 1-triazole carboxylic acid esters as metal extractants. Patent Document 4 describes the use of 1-triazole carboxylic acid esters in photographic light-sensitive materials. Patent Document 5 describes the use of 1-triazole carboxylic acid esters as synthetic intermediates for eye disease therapeutic agents. Patent Document 6 describes the carbonation reaction using 1-triazole carboxylic acid esters. In Non-Patent Document 1, 1-triazole carboxylic acid esters are described as synthetic intermediates for carbamates of β-amyloid aggregation inhibitors.

[0005] Previous technical literature

[0006] Patent Literature

[0007] Patent Document 1: WO2019 / 235635

[0008] Patent Document 2: WO2021 / 095876

[0009] Patent Document 3: U.S. Patent No. 5,254,695

[0010] Patent Document 4: Japanese Patent Application Publication No. 2003-5323

[0011] Patent Document 5: WO2010 / 088287

[0012] Patent Document 6: U.S. Patent Application Publication No. 2015 / 0133444

[0013] Non-patent literature

[0014] Non-patent literature 1: Molecules 2020, 25, 16, 3610 Summary of the invention

[0015] Technical issues to be solved by the invention

[0016] As mentioned above, in Patent Documents 1 and 2, it is described that amino lipids are synthesized by condensation of a nitrogen phenyl carbonate intermediate or a 1-imidazole carboxylate intermediate with an alcohol, but it is desired to further improve the yield of the synthesis reaction. The problem to be solved by the present invention is to provide a method for producing an amino lipid compound that improves the yield in a carbonation reaction, and an intermediate compound used in the method for producing the amino lipid compound.

[0017] Means for solving technical problems

[0018] The present inventors have conducted in-depth research to solve the above-mentioned problems and found that 1-triazole carboxylic acid ester is used as an intermediate compound and amino lipid is manufactured by condensation of 1-triazole carboxylic acid ester and alcohol, thereby improving the yield of amino lipid. The present invention is completed based on the above-mentioned insights. According to the present invention, the following invention can be provided.

[0019] <1> A compound or a salt thereof represented by the formula [1],

[0020] [Chemical formula 1]

[0021]

[0022] In the formula,

[0023] R 1 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms,

[0024] R 2 represents a divalent hydrocarbon group having 2 to 12 carbon atoms,

[0025] R 3 It represents a hydrocarbon group having 6 to 22 carbon atoms.

[0026] <2> The compound or salt thereof according to <1>, wherein R 1 It represents a hydrocarbon group having 3 to 6 carbon atoms.

[0027] <3> The compound or salt thereof according to <1> or <2>, wherein R 2 It represents a divalent hydrocarbon group having 3 to 8 carbon atoms.

[0028] <4> The compound or salt thereof according to any one of <1> to <3>, wherein R 3 It represents a hydrocarbon group having 10 to 14 carbon atoms.

[0029] <5> The compound or salt thereof according to any one of <1> to <4>, wherein R 3 Indicates -R 31 -C(R 32 )R 33 The group represented by R 31 represents a divalent hydrocarbon group having 1 to 5 carbon atoms, R 32 and R 33 Each independently represents a hydrocarbon group having 1 to 8 carbon atoms.

[0030] <6> A compound or a salt thereof represented by formula [1-1], formula [1-2], formula [1-3], formula [1-4], formula [1-5], formula [1-6], formula [1-7], formula [1-8] or formula [1-9].

[0031] [Chemical formula 2]

[0032]

[0033] <7> A method for producing a compound represented by formula [3] or a salt thereof, the method comprising the step of reacting a compound represented by formula [1] or a salt thereof as described in any one of <1> to <6> with a compound represented by formula [2] or a salt thereof,

[0034] [Chemical formula 3]

[0035]

[0036] In the formula,

[0037] R 4 and R 5 each independently represents a hydrocarbon group having 1 to 3 carbon atoms,

[0038] R 6 represents a divalent hydrocarbon group having 2 to 4 carbon atoms,

[0039] R 7 and R 8 each independently represents a divalent hydrocarbon group having 2 to 4 carbon atoms,

[0040] R 9 Represents a hydrogen atom or -COR 10 ,

[0041] R 10 represents a hydrocarbon group having 5 to 18 carbon atoms,

[0042] [Chemical formula 4]

[0043]

[0044] In the formula,

[0045] R 1 , R 2 and R 3 The definition of is the same as that in formula [1],

[0046] R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that in formula [2],

[0047] R 11 Indicates -COR 10 or

[0048] [Chemical formula 5]

[0049]

[0050] , R 10 The definition of is the same as that in formula [2], R 1 , R 2 and R 3 The definition of is the same as that in formula [1].

[0051] <8> The method according to <7>, wherein R 4 and R 5 It represents a hydrocarbon group having 2 carbon atoms.

[0052] <9> The method according to <7> or <8>, wherein R 6 It represents a divalent hydrocarbon group having 2 or 3 carbon atoms.

[0053] <10> The method according to any one of <7> to <9>, wherein R 7 and R 8 Each independently represents a divalent hydrocarbon group having 2 carbon atoms.

[0054] <11> The method according to any one of <7> to <10>, wherein R 9 Indicates -COR 10 , R 10 It represents a hydrocarbon group having 7 to 9 carbon atoms.

[0055] <12> The method according to any one of <7> to <11>, which is any one of the following (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j):

[0056] (a) the compound represented by formula [1] or a salt thereof is the compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is the compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is the compound represented by formula [3-1] or a salt thereof;

[0057] (b) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-2] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-2] or a salt thereof;

[0058] (c) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-3] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-3] or a salt thereof;

[0059] (d) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-4] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-4] or a salt thereof;

[0060] (e) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-5] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-3] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-5] or a salt thereof;

[0061] (f) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-6] or a salt thereof;

[0062] (g) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-6] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-7] or a salt thereof;

[0063] (h) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-7] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-8] or a salt thereof;

[0064] (i) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-8] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-9] or a salt thereof; or

[0065] (j) The compound represented by formula [1] or a salt thereof is a compound represented by formula [1-9] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-10] or a salt thereof.

[0066] [Chemical formula 6]

[0067]

[0068]

[0069] Effects of the Invention

[0070] According to the present invention, the yield in the carbonation reaction can be improved, and an amino lipid compound can be produced in high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 The results of analyzing the changes of the compound [2-1] under the conditions of Comparative Example 1 by silica gel thin layer chromatography are shown.

[0072] Figure 2 The results of silica gel thin layer chromatography analysis in an imidazole addition experiment are shown. DETAILED DESCRIPTION

[0073] Hereinafter, the present invention will be described in detail.

[0074] In this specification, "to" represents a range including the numerical values ​​described before and after it as the minimum value and the maximum value, respectively.

[0075] <Intermediates for producing amino lipids or their salts>

[0076] The present invention relates to a compound represented by the following formula [1] or a salt thereof. The compound represented by the formula [1] or a salt thereof can be used as an intermediate for producing an amino lipid or a salt thereof.

[0077] [Chemical formula 7]

[0078]

[0079] In the formula,

[0080] R 1 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms,

[0081] R 2 represents a divalent hydrocarbon group having 2 to 12 carbon atoms,

[0082] R 3 It represents a hydrocarbon group having 6 to 22 carbon atoms.

[0083] R 1 It preferably represents a hydrocarbon group having 2 to 10 carbon atoms, more preferably represents a hydrocarbon group having 2 to 8 carbon atoms, and still more preferably represents a hydrocarbon group having 3 to 6 carbon atoms, for example, represents a hydrocarbon group having 3 or 6 carbon atoms.

[0084] R 2 It preferably represents a divalent hydrocarbon group having 2 to 10 carbon atoms, and more preferably represents a divalent hydrocarbon group having 3 to 8 carbon atoms, for example, it represents a divalent hydrocarbon group having 3 or 8 carbon atoms.

[0085] R 3 It preferably represents a hydrocarbon group having 8 to 18 carbon atoms, more preferably represents a hydrocarbon group having 8 to 16 carbon atoms, further preferably represents a hydrocarbon group having 10 to 14 carbon atoms, and as an example, represents a hydrocarbon group having 12 carbon atoms.

[0086] R 3 Preferred representation -R 31 -C(R 32 )R 33 The group represented by R 31 represents a divalent hydrocarbon group having 1 to 5 carbon atoms, R 32 and R 33 Each independently represents a hydrocarbon group having 1 to 8 carbon atoms.

[0087] R 31 It preferably represents a divalent hydrocarbon group having 1 to 3 carbon atoms, more preferably represents a divalent hydrocarbon group having 1 to 2 carbon atoms, and further preferably represents a divalent hydrocarbon group having 1 carbon atom.

[0088] R 32 and R 33 Each independently represents more preferably a hydrocarbon group having 2 to 7 carbon atoms, and further preferably represents a hydrocarbon group having 4 to 6 carbon atoms.

[0089] As R 1The hydrocarbon group having 1 to 12 carbon atoms represented 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 straight chain or branched chain, chain or cyclic. Specific examples of the hydrocarbon group having 1 to 12 carbon atoms include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like.

[0090] As R 2 The divalent hydrocarbon group having 2 to 12 carbon atoms represented is preferably an alkylene group having 2 to 12 carbon atoms or an alkenylene group having 2 to 12 carbon atoms. The divalent hydrocarbon group having 2 to 12 carbon atoms may be a straight chain or a branched chain, and may be a chain or a ring. Specific examples of the divalent hydrocarbon group having 2 to 12 carbon atoms include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene and the like.

[0091] As R 3 The hydrocarbon group having 6 to 22 carbon atoms represented is preferably an alkyl group having 6 to 22 carbon atoms, an alkenyl group having 6 to 22 carbon atoms, or an alkynyl group having 6 to 22 carbon atoms, and more preferably an alkyl group having 6 to 22 carbon atoms. The hydrocarbon group having 6 to 22 carbon atoms may be straight chain or branched chain, and may be chain or cyclic. Specific examples of the hydrocarbon group having 6 to 22 carbon atoms include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecyl, octadecyl, nonadecyl, eicosyl, and the like.

[0092] Particularly preferred compounds as the compound represented by formula [1] or a salt thereof are compounds represented by formula [1-1], formula [1-2], formula [1-3], formula [1-4], formula [1-5], formula [1-6], formula [1-7], formula [1-8] or formula [1-9] or a salt thereof.

[0093] [Chemical formula 8]

[0094]

[0095] The compound represented by formula (1) may form a salt.

[0096] Examples of the salt in the basic group include salts with inorganic 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.

[0097] Among the above-mentioned salts, pharmaceutically acceptable salts are preferred.

[0098] The compound represented by the formula [1] can be produced by the method described in the Examples described below.

[0099] Specifically, a compound represented by the following formula [4] and 1,1′-carbonylbis(1,2,4-triazole) may be reacted in the presence of an appropriate solvent.

[0100] [Chemical formula 9]

[0101]

[0102] In the formula, R 1 , R 2 and R 3 The definition of is the same as that in formula [1].

[0103] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and for example, ethers, acetonitrile, halogenated hydrocarbons, amides and aromatic hydrocarbons can be mentioned, and these solvents can be used in combination. Preferred solvents are ethers (for example, tetrahydrofuran) or acetonitrile.

[0104] As the reaction reagent, amines such as triethylamine or 1,8-diazabicyclo[5.4.0]-7-undecene or the like can be used.

[0105] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by formula [4].

[0106] The amount of the compound represented by the formula [4] used is not particularly limited, but may be 0.1 to 10 times the molar amount of 1,1′-carbonylbis(1,2,4-triazole).

[0107] The reaction may be carried out at 0°C to 100°C, preferably 10°C to 80°C, for 10 minutes to 48 hours, preferably 1 hour to 24 hours.

[0108] <Method for producing amino lipid compound>

[0109] The present invention also relates to a method for producing a compound represented by formula [3] or a salt thereof, the method comprising the step of reacting the compound represented by formula [1] or a salt thereof with a compound represented by formula [2] or a salt thereof.

[0110] [Chemical formula 10]

[0111]

[0112] In the formula,

[0113] R 4 and R 5 each independently represents a hydrocarbon group having 1 to 3 carbon atoms,

[0114] R 6 represents a divalent hydrocarbon group having 2 to 4 carbon atoms,

[0115] R 7 and R 8 each independently represents a divalent hydrocarbon group having 2 to 4 carbon atoms,

[0116] R 9 Represents a hydrogen atom or -COR 10 ,

[0117] R 10 represents a hydrocarbon group having 5 to 18 carbon atoms,

[0118] [Chemical formula 11]

[0119]

[0120] In the formula,

[0121] R 1 , R 2 and R 3 The definition of is the same as that in formula [1],

[0122] R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that in formula [2],

[0123] R 11 Indicates -COR 10 or

[0124] [Chemical formula 12]

[0125]

[0126] , R 10 The definition of is the same as that in formula [2], R 1 , R2 and R 3 The definition of is the same as that in formula [1].

[0127] When p-nitrophenyl carbonate is used as an intermediate, DMAP (N, N-dimethylaminopyridine) needs to be added in order to carry out the carbonation reaction. However, it is considered that it is difficult to separate from DMAP by column purification in the purification process, so that the separation yield is reduced. In addition, it is considered that when 1-imidazole carboxylate is used as an intermediate, in the carbonation reaction, the imidazole that is separated as the reaction proceeds causes the inhomogenization of the ester, thereby generating a plurality of by-products, and thus the yield is reduced. In contrast, in the present invention, by using 1-triazole carboxylate represented by formula [1], the yield is improved compared with the method using p-nitrophenyl carbonate or 1-imidazole carboxylate. In the method of the present invention, since no additives are required, the yield in the purification process is not reduced, and the reactivity of the triazole that is separated as the reaction proceeds is lower than that of the imidazole, so it is presumed that the inhomogenization of the ester does not occur.

[0128] R 4 and R 5 It is preferably a hydrocarbon group having 2 carbon atoms.

[0129] R 6 It is preferably a divalent hydrocarbon group having 2 or 3 carbon atoms.

[0130] R 7 and R 8 It is preferably a divalent hydrocarbon group having 2 carbon atoms.

[0131] R 9 Preferred representation - COR 10 , R 10 It is preferably a hydrocarbon group having 7 to 9 carbon atoms.

[0132] As R 4 and R 5 The hydrocarbon group having 1 to 3 carbon atoms represented by may be any of an alkyl group, an alkenyl group or an alkynyl group, but an alkyl group is preferred. 4 and R 5 Specific examples of the hydrocarbon group having 1 to 3 carbon atoms include methyl, ethyl and propyl.

[0133] As R 6 The divalent hydrocarbon group having 2 to 4 carbon atoms represented by is preferably an alkylene group or an alkenylene group, and more preferably an alkylene group. Specific examples of the divalent hydrocarbon group having 2 to 4 carbon atoms include ethylene, trimethylene, and tetramethylene.

[0134] As R 7 and R 8The divalent hydrocarbon group having 2 to 4 carbon atoms represented by is preferably an alkylene group or an alkenylene group, and more preferably an alkylene group. Specific examples of the divalent hydrocarbon group having 2 to 4 carbon atoms include ethylene, trimethylene, and tetramethylene.

[0135] As R 10 The hydrocarbon group having 5 to 18 carbon atoms represented is preferably an alkyl group having 5 to 18 carbon atoms, an alkenyl group having 5 to 18 carbon atoms, or an alkynyl group having 5 to 18 carbon atoms, and more preferably an alkyl group having 5 to 18 carbon atoms. The hydrocarbon group having 5 to 18 carbon atoms may be a straight chain or a branched chain, and may be a chain or a ring. Specific examples of the hydrocarbon group having 5 to 18 carbon atoms include pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and the like.

[0136] In the method for producing an amino lipid compound of the present invention, any one of the following (a), (b), (c), (d), (e) or (f) is particularly preferred.

[0137] (a) the compound represented by formula [1] or a salt thereof is the compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is the compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is the compound represented by formula [3-1] or a salt thereof;

[0138] (b) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-2] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-2] or a salt thereof;

[0139] (c) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-3] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-3] or a salt thereof; or

[0140] (d) The compound represented by formula [1] or a salt thereof is a compound represented by formula [1-4] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-4] or a salt thereof.

[0141] (e) The compound represented by formula [1] or a salt thereof is a compound represented by formula [1-5] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-3] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-5] or a salt thereof.

[0142] (f) The compound represented by formula [1] or a salt thereof is the compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is the compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is the compound represented by formula [3-6] or a salt thereof.

[0143] (g) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-6] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-7] or a salt thereof;

[0144] (h) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-7] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-8] or a salt thereof;

[0145] (i) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-8] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-9] or a salt thereof; or

[0146] (j) The compound represented by formula [1] or a salt thereof is a compound represented by formula [1-9] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-10] or a salt thereof.

[0147] [Chemical formula 13]

[0148]

[0149]

[0150] The reaction of the compound represented by the formula [1] or a salt thereof with the compound represented by the formula [2] or a salt thereof can be carried out according to the method described in the Examples described later.

[0151] Specifically, the compound represented by the formula [1] or a salt thereof may be reacted with the compound represented by the formula [2] or a salt thereof in the presence of a suitable solvent and a suitable base.

[0152] The solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and for example, ethers, acetonitrile, halogenated hydrocarbons, amides and aromatic hydrocarbons can be mentioned, and these solvents can be used in combination. Preferred solvents are ethers (for example, tetrahydrofuran) or acetonitrile.

[0153] The base is preferably an organic base, and amines such as triethylamine or 1,8-diazabicyclo[5.4.0]-7-undecene can be used.

[0154] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound represented by formula [1].

[0155] The amount of the compound represented by the formula [1] used is not particularly limited, and may be 0.1 to 10 times the molar amount of the compound represented by the formula [2].

[0156] The reaction may be carried out at 0°C to 100°C, preferably 10°C to 80°C, for 10 minutes to 48 hours, preferably 1 hour to 36 hours.

[0157] <Application of amino lipids>

[0158] The amino lipid or its salt produced by the manufacturing method of the present invention can be used to prepare lipid particles. When preparing lipid particles, in addition to the amino lipid or its salt, at least one lipid selected from the group consisting of sterols, neutral lipids and lipids with nonionic hydrophilic polymer chains can also be used. Nucleic acids can also be included in lipid particles.

[0159] In the lipid particles, the amount of the 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 mass.

[0160] Sterol is not particularly limited, and cholesterol, phytosterol (sitosterol, stigmasterol, fucosterol, spinasterol, rapeseed sterol, etc.), ergosterol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, etc. can be cited. Among these, cholesterol is preferred. The amount of sterol is preferably 10mol% to 60mol%, more preferably 20mol% to 55mol%, and further preferably 25mol% to 50mol% relative to the total lipid mass.

[0161] The neutral lipid is not particularly limited, and phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, etc. can be cited, preferably phosphatidylcholine and phosphatidylethanolamine. In addition, the neutral lipid can be a single neutral lipid or a combination of multiple different neutral lipids. In the lipid particles, the amount of the neutral lipid is preferably 3 mol% or more and 55 mol% or less relative to the total amount of the lipid components.

[0162] Examples of nonionic hydrophilic polymers in lipids with nonionic hydrophilic polymer chains are not particularly limited, and include nonionic vinyl polymers, nonionic polyamino acids, nonionic polyesters, nonionic polyethers, nonionic natural polymers, nonionic modified natural polymers, and block polymers or graft copolymers with two or more of these polymers as constituent units. Among these nonionic hydrophilic polymers, nonionic polyethers, nonionic polyesters, nonionic polyamino acids, or nonionic synthetic polypeptides are preferred, nonionic polyethers or nonionic polyesters are further preferred, nonionic polyethers or nonionic monoalkoxy polyethers are further preferred, and polyethylene glycol (hereinafter, polyethylene glycol is also referred to as PEG) is particularly preferred.

[0163] The lipid having a nonionic hydrophilic polymer is not particularly limited, and examples thereof include PEG-modified phosphoethanolamine, diacylglycerol PEG derivatives, dialkylglycerol PEG derivatives, cholesterol PEG derivatives, ceramide PEG derivatives, etc. Among these, diacylglycerol PEG is preferred.

[0164] 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.

[0165] The nonionic hydrophilic polymer chain may be branched or may have a substituent such as a hydroxymethyl group.

[0166] 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%, based on the total lipid mass.

[0167] The lipid particles may contain nucleic acids. Examples of nucleic acids include plasmids, single-stranded DNA, double-stranded DNA, siRNA (small interfering RNA), miRNA (micro RNA), mRNA, antisense oligonucleotides, ribozymes, aptamers, saRNA, sgRNA, etc., and any of them may be included. In addition, modified nucleic acids may also be included. As nucleic acids, RNA is particularly preferred, and RNA having a base number of 5 to 20,000 bases is preferred.

[0168] In the lipid particles, the mass ratio of lipid to nucleic acid is preferably 2 to 1,000, more preferably 3 to 500, further preferably 5 to 200, and particularly preferably 5 to 100.

[0169] The manufacturing method of lipid particles is not particularly limited, and can be manufactured by dissolving all or part of the oil-soluble components of the constituents of lipid particles in an organic solvent etc. as an oil phase, and dissolving the water-soluble components in water as an aqueous phase, and mixing the oil phase and the aqueous phase. In the mixing, a micro mixer can be used, and emulsifiers such as homogenizers, ultrasonic emulsifiers, high-pressure jet emulsifiers etc. can also be used for emulsification.

[0170] Alternatively, lipid particles can be produced by preparing a dry mixture containing lipids by drying a solution containing lipids under reduced pressure using an evaporator or the like or spray drying using a spray dryer or the like, and adding the mixture to an aqueous solvent and further emulsifying it using the aforementioned emulsifier or the like.

[0171] An example of a method for producing lipid particles containing nucleic acids includes a method comprising the following steps:

[0172] (a) dissolving the constituent components of lipid particles containing the compound of the present invention in an organic solvent to obtain an oil phase;

[0173] A step (b) of mixing the oil phase obtained in the step (a) and the aqueous phase containing nucleic acid;

[0174] A step (c) of diluting the mixed solution comprising the oil phase and the aqueous phase obtained in the step (b) to obtain a dispersion solution of nucleic acid lipid particles; and

[0175] A step (d) of removing the organic solvent from the dispersion of nucleic acid-lipid particles obtained in the step (c).

[0176] Lipid particles refer to particles composed of lipids, including compositions having any structure selected from lipid aggregates, micelles, and liposomes formed by lipid aggregation, but as long as it is a composition containing lipids, the structure of the lipid particles is not limited to these. As liposomes, there are the following: liposomes having a lipid bilayer structure, having an aqueous phase inside, and double membranes as single layers; multiphase liposomes overlapped in multiple layers. Any liposome can be included in the present invention.

[0177] The morphology of lipid particles can be confirmed by electron microscopic observation or structural analysis using X-rays. For example, by using the method of Cryo transmission electron microscopy (CryoTEM method), it can be confirmed whether the lipid particles have a lipid bimolecular membrane structure (lamellar structure) and an inner water layer, such as liposomes, or whether there is a core with a high electron density inside the particle and filled with a structure of constituents headed by lipids. By measuring with small angle X-ray scattering (SAXS), it is also possible to confirm the presence or absence of lipid bimolecular membrane structure (lamellar structure) for lipid particles.

[0178] As an example of utilizing lipid particles, by introducing the lipid particles comprising nucleic acid into cells, nucleic acid (e.g., gene, etc.) can be introduced into cells. And, when the lipid particles in the present invention include nucleic acid with pharmaceutical use, the lipid particles can be administered to a living body as a nucleic acid drug.

[0179] Lipid granules can keep nucleic acid with high encapsulation rate, so it is very useful as nucleic acid delivery vector.According to utilizing nucleic acid delivery vector of the present invention, for example, nucleic acid etc. can be introduced into cell by in vitro (in vitro) or in vivo (in vivo) transfection by mixing the obtained lipid granules with nucleic acid etc. Nucleic acid delivery vector is also useful as the nucleic acid delivery vector in nucleic acid drug.That is, lipid granules are useful as the composition for delivering nucleic acid in vitro (in vitro) or in vivo (in vivo) (preferably invivo (in vivo)).

[0180] Next, the present invention will be described with reference to Examples, but the present invention is not limited to these.

[0181] Example

[0182] Unless otherwise specified, purification by silica gel column chromatography used an automatic purification apparatus ISOLERA (Biotage), a medium-pressure fractionation purification apparatus Purif-espoir-2 (Shoko Science Co., Ltd.), a medium-pressure liquid chromatograph YFLC W-prep 2XY (YAMAZEN CORPORATION) or a glass open column chromatography tube.

[0183] Unless otherwise specified, the carrier used in the silica gel column chromatography was Chromatorex Q-Pack SI 50 (FUJI SILYSIA CHEMICAL LTD.), HIGH FLASH COLUMN W001, W002, W003, W004 or W005 (YAMAZEN CORPORATION), WakoSil C-200 (FUJIFIL M Wako Pure Chemical Corporation), or CHROMATOREX PSQ 100B (FUJI SILYSIA CHEMICAL LTD.).

[0184] As the NH silica gel, Chromatorex Q-Pack NH 60 (FUJI SILYSIA CHEMICAL LT D.) and CHROMATOREX NH-DM1020 (FUJI SILYSIA CHEMICAL LTD.) were used.

[0185] The NMR spectrum was measured using AVNEO400 (manufactured by Bruker) using tetramethylsilane as an internal standard, and the total δ value was expressed in ppm.

[0186] The MS spectrum was measured using ACQUITY SQD LC / MS System (manufactured by Waters).

[0187] [Example 1] (1)

[0189] [Chemical formula 14]

[0190]

[0191] Under ice cooling, dimethyl sulfoxide (125 mL), toluene (105 mL) and powdered potassium hydroxide (16.6 g) were added with di-tert-butyl malonate (25.00 g), stirred at the same temperature for 10 minutes, and then 1-bromopentane (41.9 g) was added, and stirred at room temperature for 5 hours. Under ice cooling, 7% hydrochloric acid (160 g) was added dropwise to the reaction mixture, and the organic layer was separated and washed with water (50 g) and 20% sodium chloride aqueous solution (60 g). After drying with anhydrous sodium sulfate (50 g), the solvent was distilled off under reduced pressure to obtain di-tert-butyl 2,2-dipentylmalonate (54.8 g) as a light yellow oil.

[0192] 1H-NMR(CDCl3)δ:1.80-1.74(4H,m),1.44(18H,s),1.36-1.23(8H,m),1.18-1.09(4H,m),0.87(6H,t,J=7.0Hz).

[0193] Water (5.4 mL), toluene (54 mL) and trifluoroacetic acid (108 mL) were added to the obtained di-tert-butyl 2,2-dipentylmalonate (54.4 g), and stirred at room temperature for 2 hours. After the solvent of the reaction mixture was distilled off under reduced pressure, hexane (88 mL) was added and stirred for 30 minutes under ice cooling. After filtering the solid matter, it was washed with hexane to obtain 2,2-dipentylmalonate (15.4 g) as a white solid.

[0194] 1 H-NMR(CDCl3)δ:1.98-1.91(4H,m),1.35-1.22(12H,m),0.87(6H,t,J=7.0Hz).

[0195] 2,2-Dipentylmalonic acid (18.0 g) was stirred without solvent at 165° C. for 3 hours and then cooled to room temperature to obtain 2-pentylheptanoic acid (14.8 g) as a light yellow oil.

[0196] 1 H-NMR(CDCl3)δ:2.39-2.31(1H,m),1.67-1.56(2H,m),1.52-1.42(2H,m),1.36-1.22(12H,m),0.90-0.85(6H,m).

[0197] Under ice-cooling, a solution of 2-pentylheptanoic acid (98.5 g) in tetrahydrofuran (200 mL) was added dropwise to a mixture of lithium aluminum hydride (39.2 g) and tetrahydrofuran (800 mL), followed by stirring at room temperature for 1 hour. Under ice-cooling, sodium sulfate decahydrate (200 g) was added to the reaction mixture, followed by stirring at room temperature for 5 hours. After filtering out the insoluble matter, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-pentylheptane-1-ol (89.1 g) as a light yellow oil.

[0198] 1 H-NMR(CDCl3)δ:3.57-3.51(2H,m),1.50-1.20(17H,m),0.88(6H,t,J=6.6Hz). (2)

[0200] [Chemical formula 15]

[0201]

[0202] Under ice cooling, a mixture of 20% hexylmagnesium bromide-tetrahydrofuran solution (510 g) and tetrahydrofuran (260 mL) was added dropwise to a solution of glutaric anhydride (68.1 g) in tetrahydrofuran (255 mL), and stirred at the same temperature for 30 minutes, and then 7% hydrochloric acid (540 mL) was added dropwise. Hexane (480 mL) was added, and after stirring at room temperature for 5 minutes, the organic layer was separated, washed with water (240 mL), and then a mixture of potassium hydroxide (74.9 g), methanol (375 mL) and water (780 mL) was added, and the aqueous layer was separated. After washing with methyl tert-butyl ether (370 mL), 30% hydrochloric acid (190 mL) was added under ice cooling, and then ethyl acetate (375 mL) was added, and the organic layer was separated and washed with water (140 mL). After drying with anhydrous sodium sulfate (24.2 g), the solvent was distilled off under reduced pressure. Methanol (560 mL) was added to the obtained brown solid (67.7 g), and water (1700 mL) was added dropwise, and then stirred for 10 minutes under ice-cooling. After filtering the solid, it was washed 3 times with water (190 mL) to obtain a light brown solid (48.9 g). Methyl tert-butyl ether (90 mL) was added to the obtained light brown solid (44.9 g), and after stirring at 40° C., hexane (360 mL) was added and stirred under ice-cooling. After filtering the solid, it was washed 3 times with hexane (180 mL) to obtain 5-oxoundecanoic acid (31.1 g) as a white solid.

[0203] 1 H-NMR(CDCl3)δ: 2.50(2H,t,J=7.2Hz), 2.40(4H,t,J=7.2Hz), 2.02-1.80(2H,m), 1.63-1.48(2H,m), 1.37-1.20(6H,m), 0.88(3H,t,J=6.6Hz).

[0204] To a mixture of 5-oxoundecanoic acid (40.8 g), 2-pentyl-1-heptanol (33.0 g) and toluene (165 mL) was added p-toluenesulfonic acid monohydrate (1.7 g), and stirred under heating reflux for 4 hours. After the reaction mixture was cooled to room temperature, hexane (150 mL) and water (300 mL) were added, and the organic layer was separated. After washing with water (300 mL) twice, it was washed with a saturated sodium chloride aqueous solution (300 mL). After drying with anhydrous sodium sulfate (50 g), the solvent was distilled off under reduced pressure to obtain 2-pentylheptyl 5-oxoundecanoic acid ester (75.5 g) of a light yellow oily substance.

[0205] 1H-NMR(CDCl3)δ: 3.97(2H,d,J=5.1Hz), 2.47(2H,t,J=7.2Hz), 2.39(2H,t,J=7.2Hz), 2.33(2 H,t,J=7.2Hz),1.95-1.83(2H,m),1.66-1.49(3H,m),1.36-1.20(22H,m),0.92-0.82(9H,m).

[0206] Toluene (375 mL) was added to the obtained 2-pentylheptyl 5-oxondecanoate (75.5 g), sodium borohydride (5.8 g) was added under ice-cooling, and methanol (75 mL) was added dropwise under the same temperature condition, and stirred for 1 hour. Hexane (500 mL) and 1 mol / L hydrochloric acid (250 mL) were added to the reaction mixture under the same temperature condition, and water (200 mL) was added to separate the organic layer. After washing with water (500 mL) twice, washing with a saturated sodium chloride aqueous solution (300 mL) once, and drying with anhydrous sodium sulfate (50 g), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-pentylheptyl 5-hydroxyundecanoate (48.9 g) as a colorless oil.

[0207] 1 H-NMR (CDCl3) δ: 3.98 (2H, d, J = 6.0Hz), 3.63-3.57 (1H, m), 2.41-2.28 (2H, m), 1.84-1.22 (32H, m), 0.88 (9H, t, J = 7.2Hz). (3)

[0209] [Chemical formula 16]

[0210]

[0211] 2-Bromo-N,N-diethylethane-1-amine hydrobromide (500.1 g) was added to a solution of 2-aminoethanol (351.5 g) in 1,2-dimethoxyethane (1.8 L), and the mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate (1 L) was added to the obtained residue, and then a solution of potassium carbonate (540 g) in water (600 g) was added, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, ethyl acetate (500 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1 L). The organic layer and the extract were dried over anhydrous sodium sulfate (200 g), and the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure to obtain 2-((2-(diethylamino)ethyl)amino)-1-ethanol (109.2 g) as a colorless oil.

[0212] 1 H-NMR(CDCl3)δ:3.65-3.61(2H,m),2.80-2.76(2H,m),2.69(2H,t,J=4.0Hz),2.56-2.50(6H,m),1.02(6H,t,J=8.0Hz).

[0213] MS m / z(M+H):161. (4)

[0215] [Chemical formula 17]

[0216]

[0217] Under ice cooling, a mixture of triethylamine (28.1 g), 4-dimethylaminopyridine (0.16 g) and tetrahydrofuran (28 mL) was added dropwise to a mixture of decanoyl chloride (50.0 g), tetrahydrofuran (200 mL) and 2-bromoethane-1-ol (33.1 g), and stirred at room temperature for 3 hours. Water (250 mL) and toluene (750 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with 2 mol / L hydrochloric acid (250 mL), water (250 mL) and saturated sodium chloride aqueous solution (125 mL), dried with anhydrous sodium sulfate (150 g), and then the solvent was removed by reduced pressure distillation. NH silica gel (50 g) and toluene (250 mL) were added to the residue, and stirred at room temperature for 10 minutes. After filtering out the insoluble matter, the solvent was removed by reduced pressure distillation to obtain 2-bromoethyl decanoate (69.0 g) as a light yellow oil.

[0218] 1H-NMR(CDCl3)δ: 4.39(2H,t,J=6.2Hz), 3.51(2H,t,J=6.2Hz), 2.35(2H,t,J=7.6Hz), 1.67-1.60(2H,m), 1.33-1.26(12H,m), 0.88(3H,t,J=6.8Hz).

[0219] After adding N,N-dimethylformamide (50 mL) to the obtained 2-bromoethyl decanoate (40.0 g), 2-((2-(diethylamino)ethyl)amino)-1-ethanol (27.8 g), finely powdered potassium carbonate (23.9 g) and potassium iodide (7.2 g) crushed in a mortar were added, and stirred at 60°C for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (400 mL) and water (400 mL) were added, and the organic layer was separated. After washing with 6% sodium bicarbonate aqueous solution (200 mL) and saturated sodium chloride aqueous solution (100 mL), and drying with anhydrous sodium sulfate (30.8 g), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel) to obtain compound [2-1] (40.1 g) as a colorless oil.

[0220] 1 H-NMR(CDCl3)δ:4.15(2H,t,J=6.0Hz),3.54(2H,t,J=5.0Hz),2.84(2H,t,J=6.0Hz),2.70-2.65(4H,m),2.54(4H,q,J=7.2Hz),2 .48(2H,t,J=6.0Hz), 2.30(2H,t,J=7.6Hz), 1.65-1.58(2H,m), 1.34-1.20(12H,m), 1.03(6H,t,J=7.2Hz), 0.88(3H,t,J=7.0Hz).

[0221] MS m / z(M+H):359. (5)

[0223] [Chemical formula 18]

[0224]

[0225] 1,1'-Carbonylbis(1,2,4-triazole) (22.6 g) was added to a tetrahydrofuran (170 mL) solution of 2-pentylheptyl 5-hydroxyundecanoate (34.0 g), and the mixture was stirred at 30°C for 4 hours. Water (170 mL) was added dropwise to the reaction mixture, and then hexane (170 mL) and ethyl acetate (85 mL) were added to separate the organic layer. The mixture was washed with a 15% aqueous sodium chloride solution (200 mL), dried with anhydrous sodium sulfate (34 g), and the solvent was distilled off under reduced pressure to obtain compound [1-1] (45.2 g).

[0226] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0227] Tetrahydrofuran (83 mL), a tetrahydrofuran (68 mL) solution of compound [2-1] (37.8 g) and triethylamine (18.6 g) were added to the obtained compound [1-1] (44.8 g), and stirred at 50° C. for 24 hours. The reaction mixture was cooled to 30° C., ethyl acetate (170 mL), hexane (170 mL) and water (170 mL) were added, and the organic layer was separated. After washing with water (170 mL) and 20% sodium chloride aqueous solution (200 mL), and drying with anhydrous sodium sulfate (80.1 g), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-1] (57.5 g, yield 83% (2 steps)) as a light yellow oil.

[0228] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97

[0229] (2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2.55-2.48(6H,m),2.35-2.27(4 H,m),1.71-1.55(9H,m),1.36-1.20(36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0230] MS m / z(M+H):755.

[0231] [Example 2]

[0232] [Chemical formula 19]

[0233]

[0234] 1,1'-Carbonylbis(1,2,4-triazole) (1.7 g) was added to a tetrahydrofuran (13 mL) solution of 2-butyloctyl 5-hydroxyundecanoate (2.5 g), and the mixture was stirred at 30°C for 3 hours. Water (52 mL) and hexane (52 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with water (52 mL) and a saturated sodium chloride aqueous solution (52 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain compound [1-2] (3.2 g).

[0235] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0236] Tetrahydrofuran (15 mL), compound [2-1] (2.9 g) and triethylamine (1.3 g) were added to the obtained compound [1-2] (3.0 g), and stirred at 50° C. for 24 hours. The reaction mixture was cooled to 30° C., ethyl acetate (30 mL) and water (30 mL) were added, and the organic layer was separated. The mixture was washed with water (30 mL) and a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-2] (4.1 g, yield 85% (2 steps)) as a light yellow oil.

[0237] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97

[0238] (2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2.55-2.48(6H,m),2.35-2.27(4H,m),1.71-1.55(9H,m),1.36-1.20

[0239] (36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0240] MS m / z(M+H):755.

[0241] [Example 3] (1)

[0243] [Chemical formula 20]

[0244]

[0245] Under ice-cooling, triethylamine (102.1 g) and anhydrous magnesium chloride (80.1 g) were added to a mixture of potassium monoethyl malonate (114.5 g) and tetrahydrofuran (900 mL), and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, heptanoyl chloride (50.0 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Under ice-cooling, a solution of citric acid (193 g) in water (1 L) was added to the reaction mixture, and toluene (500 mL) was added to separate the organic layer. The mixture was washed once with water (500 mL), washed twice with a 5% sodium bicarbonate aqueous solution (500 mL), washed once with a saturated sodium chloride aqueous solution (150 mL), dried with anhydrous sodium sulfate (200 g), and the solvent was removed by distillation under reduced pressure to obtain ethyl 3-oxononanoate (67.8 g) as a light yellow oil.

[0246] 1 H-NMR (CDCl3) δ: 4.20 (2H, q, J = 8.0Hz), 3.43 (2H, s), 2.53 (2H, t, J = 8.0Hz), 1.65-1.52 (2H, m), 1.26-1.21 (9H, m), 0.88 (3H, t, 8.0Hz).

[0247] After adding ethanol (40 mL) to the obtained ethyl 3-oxononanoate (67.4 g), 20% sodium ethoxide-ethanol solution (117.8 g) was added, and ethyl 8-bromooctanoate (83.7 g) was added dropwise, and stirred at 90° C. for 6 hours. After the reaction mixture was cooled to room temperature, a solution of sodium hydroxide (33.0 g) in water (135 g) was added, and stirred at room temperature for 2 hours. A mixture of toluene (740 mL) and 30% hydrochloric acid (155 g) in water (135 g) was added to the reaction mixture, and stirred at 60° C. for 30 minutes. After the reaction mixture was cooled to room temperature, the organic layer was separated. After washing with water (335 mL) and saturated sodium chloride aqueous solution (335 mL), and drying with anhydrous sodium sulfate (135 g), the solvent was distilled off under reduced pressure. Hexane (630 mL) was added to the obtained residue, and after stirring at 50° C. for 1 hour, it was stirred at 0° C. for 1 hour. The solid substance was collected by filtration and then washed with hexane (250 mL) to obtain 10-oxohexadecanoic acid (36.0 g) as a light yellow solid.

[0248] 1 H-NMR(CDCl3)δ: 2.45-2.28(6H,m), 1.71-1.47(6H,m), 1.40-1.20(14H,m), 0.88(3H,t,J=8.0Hz).

[0249] To a mixture of 10-oxohexadecanoic acid (25.0 g), 2-pentyl-1-heptanol (15.0 g) and toluene (105 mL), p-toluenesulfonic acid monohydrate (1.5 g) was added and stirred for 6 hours under heating reflux. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution (105 mL) was added and stirred for 5 minutes. Insoluble matter was filtered off, hexane (105 mL) and water (50 mL) were added, and the organic layer was separated. After washing with a saturated sodium bicarbonate aqueous solution (105 mL) and a saturated sodium chloride aqueous solution (30 mL), and drying with anhydrous sodium sulfate (20 g), the solvent was removed by reduced pressure distillation to obtain 2-butyloctyl 10-oxohexadecanoate (34.1 g) as a light yellow oil.

[0250] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.8Hz), 2.37 (4H, t, J = 7.4Hz), 2.29 (2H, t, J = 7.5Hz), 1.63-1.52 (7H, m), 1.40-1.19 (30H, m), 0.96-0.81 (9H, m).

[0251] Toluene (170 mL) was added to the obtained 2-butyloctyl 10-oxohexadecanate (34.0 g), and then sodium borohydride (2.2 g) was added under ice-cooling, and methanol (22 mL) was added dropwise under the same temperature condition, and stirred for 3 hours under the same temperature condition. A mixture of hexane (170 mL) and 30% hydrochloric acid (6.8 mL) in water (160 mL) was added to the reaction mixture, and the organic layer was separated. The mixture was washed twice with water (170 mL), washed once with a saturated sodium chloride aqueous solution (64 mL), dried with anhydrous sodium sulfate (34 g), and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-butyloctyl 10-hydroxyhexadecanoate (24.9 g) as a light yellow oil.

[0252] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.8Hz), 3.63-3.52 (1H, m), 2.30 (2H, t, J = 7.5Hz), 1.68-1.21 (42H, m), 0.96-0.81 (9H, m). (2)

[0254] [Chemical formula 21]

[0255]

[0256] Ethanolamine (500 mL) was added to a mixture of 2-chloro-N,N-diethylethane-1-amine hydrochloride (520 g) and 1,4-dioxane (2 L), and the mixture was stirred for 4 hours under heating and reflux. The solvent of the reaction mixture was removed by distillation under reduced pressure, and ethyl acetate (2 L) was added to the residue, followed by a 45% aqueous potassium carbonate solution (680 mL), and the mixture was stirred for 30 minutes. Insoluble matter was filtered off, and the solvent was removed by distillation under reduced pressure. The residue obtained was purified by distillation under reduced pressure to obtain 2-((2-(diethylamino)ethyl)amino)-1-ethanol (300 g) as a colorless oil.

[0257] 1 H-NMR(CDCl3)δ:3.65-3.61(2H,m),2.80-2.76(2H,m),2.69(2H,t,J=4.0Hz),2.56-2.50(6H,m),1.02(6H,t,J=8.0Hz).MS m / z(M+H): 161. (3)

[0259] [Chemical formula 22]

[0260]

[0261] Under ice cooling, octanoyl chloride (72.7 g) was added dropwise to a mixture of 2,2-diethoxy-1-ethanol (50.0 g), triethylamine (49.0 g) and toluene (500 mL), and the mixture was stirred at room temperature for 2.5 hours. Under ice cooling, water (500 mL) was added dropwise to the reaction mixture, and the organic layer was separated. After washing with 10% potassium carbonate aqueous solution (500 mL), water (200 mL) and 20% sodium chloride aqueous solution (250 mL), NH silica gel (97.0 g) and anhydrous sodium sulfate (200 g) were added, and the mixture was stirred for 1 hour. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure to obtain 2,2-diethoxyethyl octanoate (98.6 g) as a yellow oil.

[0262] 1 H-NMR(CDCl3)δ:4.68(1H,t,J=4.0Hz), 4.10(2H,d,J=4.0Hz), 3.72(1H,q,J=6.8Hz), 3.69(1H,q,J=6.8Hz, 3.58(1H,q,J=6.8Hz), 3.56(1H,q,J=6.8Hz), 2.34(2H,t,J=7.6Hz), 1.67-1.57(2H,m), 1.37-1.21(8H,m), 1.22(6H,t,J=6.8Hz), 0.88(3H,t,J=7.2Hz).

[0263] To a mixture of 2,2-diethoxyethyl octanoate (40.0 g) and water (20 mL) was added formic acid (80 mL), and the mixture was stirred at 30°C for 3 hours. Ethyl acetate (600 mL) and a solution of sodium chloride (100 g) in water (400 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed twice with a mixture of potassium carbonate (80 g), sodium chloride (20 g), and water (400 g), and once with a solution of sodium chloride (100 g) in water (400 mL), and then anhydrous sodium sulfate (200 g) was added, and the mixture was stirred at room temperature for 2 hours. The insoluble matter was filtered off to obtain an ethyl acetate solution of 2-oxoethyl octanoate.

[0264] 1 H-NMR(CDCl3)δ:9.61(1H,s),4.67(2H,s),2.45(2H,t,J=7.6Hz),1.76-1.57(2H,m),1.39-1.19(8H,m),0.88(3H,t,J=7.2Hz).

[0265] Under ice cooling, a solution of 2-((2-(diethylamino)ethyl)amino)-1-ethanol (29.1 g) in ethyl acetate (100 mL) was added dropwise to the obtained ethyl acetate solution of 2-oxoethyl octanoate, and then sodium triacetoxyborohydride (48.1 g) was added, followed by stirring at room temperature for 2 hours. Under ice cooling, a solution of potassium carbonate (155.3 g) in water (800 g) was added dropwise to the reaction mixture, and the organic layer was separated. After washing with a solution of potassium carbonate (80 g) in water (800 g) and a solution of sodium chloride (60 g) in water (200 g), 1% hydrochloric acid (800 g) was added, the aqueous layer was separated, and the obtained aqueous layer was washed with ethyl acetate (200 mL). Under ice cooling, the obtained hydrochloric acid mixture was added dropwise to a mixture of ethyl acetate (500 mL), potassium carbonate (90.3 g) and water (600 g), and the organic layer was separated and washed with a saturated sodium chloride aqueous solution (150 mL). Anhydrous sodium sulfate (200 g) was added and stirred at room temperature for 1 hour. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain compound [2-2] (30.2 g) as a colorless oil.

[0266] 1 H-NMR(CDCl3)δ:5.20(1H,brs),4.15(2H,t,J=6.0Hz),3.54(2H,t,J=4.8Hz),2.84(2H,t,J=6.0Hz),2.70-2.64(4H,m),2.54(4H,q,J=7 .2Hz), 2.47(2H,t,J=6.0Hz), 2.30(2H,t,J=7.6Hz), 1.66-1.55(2H,m), 1.34-1.22(8H,m), 1.03(6H,t,J=7.2Hz), 0.88(3H,t,J=7.0Hz).

[0267] MS m / z(M+H):331. (4)

[0269] [Chemical formula 23]

[0270]

[0271] 1,1'-Carbonylbis(1,2,4-triazole) (5.9 g) was added to a tetrahydrofuran (53 mL) solution of 2-butyloctyl 10-hydroxyhexadecanoate (10.6 g), and the mixture was stirred at 30°C for 3 hours. Water (50 mL), ethyl acetate (50 mL) and hexane (50 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with water (50 mL) and a saturated sodium chloride aqueous solution (25 mL), dried over anhydrous sodium sulfate (40 g), and the solvent was distilled off under reduced pressure to obtain compound [1-3] (13.5 g).

[0272] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(34H,m),0.91-0.85(9H,m).

[0273] Tetrahydrofuran (52 mL), compound [2-2] (8.8 g) and triethylamine (4.9 g) were added to the obtained compound [1-3] (13.0 g), and stirred at 50° C. for 25 hours. The reaction mixture was cooled to 30° C., ethyl acetate (52 mL), hexane (52 mL) and water (52 mL) were added, and the organic layer was separated. The mixture was washed with water (52 mL) and a saturated aqueous sodium chloride solution (52 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-3] (14.9 g, yield 77% (2 steps)) as a light yellow oil.

[0274] 1 H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.20-4.08(4H,m),3.97

[0275] (2H,d,J=5.6Hz),2.89-2.77(4H,m),2.73-2.42(8H,m),2.29(4H,t,J=7.6Hz), 1.68-1.48(9H,m),1.39-1.18(42H,m),1.10-0.98(6H,m),0.94-0.81(12H,m).

[0276] MS m / z(M+H):798.

[0277] [Example 4] (1)

[0279] [Chemical formula 24]

[0280]

[0281] Under ice cooling, dimethyl malonate (100.0 g) was added to a mixture of dimethyl sulfoxide (750 mL), toluene (750 mL) and powdered potassium hydroxide (109.9 g), and stirred at room temperature for 10 minutes, followed by the addition of 1-bromopentane (274.4 g), and stirred at room temperature for 5 hours. Under ice cooling, 7% hydrochloric acid (900 mL) was added dropwise to the reaction mixture, and the organic layer was separated and washed with water (200 mL) and a 10% sodium chloride aqueous solution. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2,2-dipentylmalonate (201.6 g) as a light yellow oil.

[0282] 1 H-NMR(CDCl3)δ:3.70(6H,s),1.89-1.83(4H,m),1.35-1.22(8H,m),1.17-1.08(4H,m),0.87(6H,t,J=7.0Hz).

[0283] Tetrahydrofuran (430 mL), methanol (430 mL) and a water (430 mL) solution of potassium hydroxide (260 g) were added to the obtained dimethyl 2,2-dipentylmalonate (179.0 g), and stirred at 70°C for 34 hours. The reaction mixture was cooled to room temperature, 15% hydrochloric acid (880 mL) was added dropwise under ice-cooling, and ethyl acetate (420 mL) was added to separate the organic layer. After washing with 5% sodium bicarbonate aqueous solution (420 mL), and drying with anhydrous sodium sulfate (100 g), the solvent was distilled off under reduced pressure. Hexane (480 mL) and ethyl acetate (48 mL) were added to the obtained residue, and stirred for 1 hour under ice-cooling. After filtering the solid matter, it was washed with hexane (200 mL) to obtain 2,2-dipentylmalonate (105.1 g) as a white solid.

[0284] 1 H-NMR(CDCl3)δ:1.98-1.91(4H,m),1.35-1.22(12H,m),0.87(6H,t,J=7.0Hz).

[0285] A mixture of 2,2-dipentylmalonic acid (100.0 g) and pyridine (500 mL) was stirred for 8 hours under heating and reflux. The solvent of the reaction mixture was distilled off under reduced pressure, and ethyl acetate (200 mL), hexane (200 mL) and 10% hydrochloric acid (200 mL) were added to the obtained residue to separate the organic layer. After washing with water (200 mL) and drying with anhydrous sodium sulfate (20 g), the solvent was distilled off under reduced pressure to obtain 2-pentylheptanoic acid (81.6 g) as a light yellow oil.

[0286] 1 H-NMR(CDCl3)δ:2.39-2.31(1H,m),1.67-1.56(2H,m),1.52-1.42(2H,m),1.36-1.22(12H,m),0.90-0.85(6H,m).

[0287] Under ice-cooling, isobutyl chloroformate (6.5 g) was added dropwise to a mixture of 2-pentylheptanoic acid (8.5 g), 4-methylmorpholine (5.2 g) and tetrahydrofuran (42.5 mL), and the mixture was stirred at the same temperature for 30 minutes. Water (42.5 mL) was added to the reaction mixture, and the organic layer was separated and washed with water (42.5 mL) to obtain a tetrahydrofuran mixture. Tetrahydrofuran (21.3 mL) was added to the obtained tetrahydrofuran mixture, and sodium borohydride (3.53 g) was added under ice-cooling. After stirring at the same temperature for 10 minutes, methanol (12.8 mL) was added, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, 10% ammonium chloride aqueous solution (80 mL) was added to the reaction mixture, and after stirring at room temperature for 5 minutes, hexane (42.5 mL) was added, and the organic layer was separated. After washing with water and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure to obtain 2-pentylheptan-1-ol (3.7 g) as a pale yellow oily substance.

[0288] 1 H-NMR(CDCl3)δ:3.57-3.51(2H,m),1.50-1.20(17H,m),0.88(6H,t,J=6.6Hz). (2)

[0290] [Chemical formula 25]

[0291]

[0292] 1,1'-Carbonylbis(1,2,4-triazole) (3.8 g) was added to a tetrahydrofuran (34 mL) solution of 2-pentylheptyl 10-hydroxyhexadecanoate (6.9 g), and the mixture was stirred at 30°C for 5 hours. Water (35 mL), ethyl acetate (20 mL) and hexane (35 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed twice with water (35 mL), once with a saturated sodium chloride aqueous solution (35 mL), and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain compound [1-4] (8.3 g).

[0293] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(34H,m),0.91-0.85(9H,m).

[0294] Tetrahydrofuran (41 mL), compound [2-2] (5.6 g) and triethylamine (3.1 g) were added to the obtained compound [1-4] (8.3 g), and stirred at 55° C. for 27 hours. The reaction mixture was cooled to 30° C., ethyl acetate (40 mL), hexane (40 mL) and water (40 mL) were added, and the organic layer was separated. The mixture was washed with water (40 mL) and a saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-4] (9.8 g, yield 79% (2 steps)) as a light yellow oil.

[0295] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.21-4.07(4H,m),3.97(2H,d,J=5.4Hz),2.88-2.77(4H,m),2.72-2.62(2H,m),2.5 8-2.45(6H,m),2.29(4H,t,J=7.2Hz),1.69-1.48(9H,m),1.41-1.18(42H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0296] MS m / z(M+H):798.

[0297] [Example 5]

[0298] [Chemical formula 26]

[0299]

[0300] 1,1'-Carbonylbis(1,2,4-triazole) (1.4 g) was added to a tetrahydrofuran (9 mL) solution of 2-pentylheptyl 5-hydroxyoctanoate (1.8 g), and the mixture was stirred at 30°C for 2 hours. Water (15 mL), ethyl acetate (3 mL) and hexane (15 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with water (15 mL) and a saturated sodium chloride aqueous solution (15 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound [1-5] (2.3 g).

[0301] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(18H,m),0.91-0.85(9H,m).

[0302] Acetonitrile (7 mL), compound [2-3] (0.50 g) and 1,8-diazabicyclo [5.4.0] -7-undecene (1.3 g) were added to the obtained compound [1-5] (2.3 g), and stirred at 50°C for 2 hours. The reaction mixture was cooled to 30°C, ethyl acetate (70 mL) and water (70 mL) were added, and the organic layer was separated. After washing with water (35 mL) and saturated sodium chloride aqueous solution (35 mL), drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-5] (1.6 g, yield 73%) as a light yellow oil.

[0303] 1 H-NMR(CDCl3)δ: 4.74-4.67(2H,m),4.22-4.10(4H,m),3.97(4H,d,J=5.6Hz),2.83(4H,t,J=6.4Hz),2.69-2.65(2H,m),2 .55-2.49(6H,m),2.34-2.30(4H,m),1.74-1.48(14H,m),1.43-1.20(36H,m),1.01(6H,t,J=7.2Hz),0.93-0.87(18H,m).

[0304] MS m / z(M+H):914.

[0305] [Example 6]

[0306] [Chemical formula 27]

[0307]

[0308] 1,1'-Carbonylbis(1,2,4-triazole) (0.66 g) was added to a tetrahydrofuran (5 mL) solution of 2-pentylheptyl 5-hydroxyundecanoate (1.0 g), and the mixture was stirred at 30°C for 2 hours. Water (10 mL), ethyl acetate (2 mL) and hexane (10 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with water (10 mL) and a saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound [1-1] (1.2 g).

[0309] 1 H-NMR(CDCl3)δ:8.82(1H,s),8.07(1H,s),5.21-5.14(1H,m),3.97(2H,d,J=5.6Hz ),2.36(2H,t,J=7.2Hz),1.88-1.55(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0310] Acetonitrile (4 mL), compound [2-4] (0.26 g) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.60 g) were added to the obtained compound [1-1] (1.2 g), and stirred at 55°C for 2 hours. The reaction mixture was cooled to 30°C, ethyl acetate (40 mL) and water (40 mL) were added, and the organic layer was separated. After washing with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [3-6] (1.1 g, yield 88%) as a light yellow oil.

[0311] 1 H-NMR(CDCl3)δ: 4.72-4.65(2H,m),4.22-4.09(4H,m),3.97(4H,d,J=6.0Hz),2.80(4H,t,J=6.4Hz),2.61-2.45(6H,m),2. 44-2.37(2H,m),2.32(4H,t,J=7.2Hz),1.74-1.49(16H,m),1.35-1.21(48H,m),1.00(6H,t,J=7.2Hz),0.91-0.85(18H,m).

[0312] MS m / z(M+H):1012.

[0313] [Example 7]

[0314] [Chemical formula 28]

[0315]

[0316] Using 2-pentylheptyl 6-hydroxydodecanoate obtained by the same method as in [Example 1] (2) as a raw material, 1-oxo-1-((2-pentylheptyl)oxy)dodec-6-yl 1H-1,2,4-triazole-1-carboxylate (compound [1-6]) was obtained by the same method as in [Example 6].

[0317] 1 H-NMR(CDCl3)δ:8.81(1H,s),8.07(1H,s),5.20-5.12(1H,m),3.95(2H,d,J=5.8Hz) ,2.31(2H,t,J=7.42Hz),1.87-1.52(7H,m),1.48-1.19(26H,m),0.92-0.83(9H,m).

[0318] The obtained compound [1-6] (0.44 g) was used as a raw material and the same method as [Example 6] was used to obtain bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-6,18-dihexyl-8,16-dioxo-7,9,15,17-tetraoxo-12-azatricosane dioic acid ester (compound [3-7] (0.34 g, yield 89%)).

[0319] 1 H-NMR(CDCl3)δ:4.71-4.62(2H,m),4.22-4.08(4H,m),3.96

[0320] (4H,d,J=5.8Hz),2.80(4H,t,J=6.4Hz),2.60-2.45(6H,m),2.44-2.37(2H,m),2.30(4H,t,J =7.5Hz),1.69-1.49(16H,m),1.44-1.18(52H,m),1.00(6H,t,J=7.1Hz),0.93-0.80(18H,m).

[0321] MS m / z(M+H):1040.

[0322] [Example 8]

[0323] [Chemical formula 29]

[0324]

[0325] Using 2-hexyloctyl 6-hydroxydodecanoate obtained by the same method as [Example 1-2] as a raw material, 1-((2-hexyloctyl)oxy)-1-oxododecan-6-yl 1H-1,2,4-triazole-1-carboxylate (Compound [1-7]) was obtained by the same method as [Example 6].

[0326] 1 H-NMR(CDCl3)δ:8.81(1H,s),8.07(1H,s),5.20-5.12(1H,m),3.95(2H,d,J=5.8Hz ),2.31(2H,t,J=7.4Hz),1.88-1.53(7H,m),1.50-1.19(30H,m),0.92-0.82(9H,m).

[0327] The obtained compound [1-7] (0.46 g) was used as a raw material, and bis(2-hexyloctyl)12-(3-(diethylamino)propyl)-6,18-dihexyl-8,16-dioxo-7,9,15,17-tetraoxo-12-azatricosane dioic acid ester (compound [3-8] (0.32 g, yield 80%)) was obtained by the same method as [Example 6].

[0328] 1 H-NMR(CDCl3)δ:4.70-4.62(2H,m),4.22-4.08(4H,m),3.96

[0329] (4H,d,J=5.8Hz),2.80(4H,t,J=6.4Hz),2.60-2.46(6H,m),2.44-2.37(2H,m),2.30(4H,t,J =7.5Hz),1.69-1.49(16H,m),1.44-1.19(60H,m),1.00(6H,t,J=7.1Hz),0.93-0.81(18H,m).

[0330] MS m / z(M+H):1096.

[0331] [Example 9]

[0332] [Chemical formula 30]

[0333]

[0334] Using 2-pentylheptyl 6-hydroxyundecanoate obtained by the same method as [Example 1-2] as a raw material, 1-oxo-1-((2-pentylheptyl)oxy)undec-6-yl 1H-1,2,4-triazole-1-carboxylate (Compound [1-8]) was obtained by the same method as [Example 6].

[0335] 1 H-NMR(CDCl3)δ:8.81(1H,s),8.07(1H,s),5.20-5.13(1H,m),3.95(2H,d,J=5.81Hz ),2.31(2H,t,J=7.4Hz),1.90-1.51(7H,m),1.50-1.19(24H,m),0.95-0.82(9H,m).

[0336] The obtained compound [1-8] (140 mg) was used as a raw material, and bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-8,16-dioxo-6,18-dipentyl-7,9,15,17-tetraoxo-12-azatricosane dioic acid ester (compound [3-9] (88 mg, yield 63%)) was obtained by the same method as [Example 6].

[0337] 1 H-NMR(CDCl3)δ:4.72-4.61(2H,m),4.22-4.07(4H,m),3.96

[0338] (4H,d,J=5.8Hz),2.80(4H,t,J=6.4Hz),2.59-2.45(6H,m),2.44-2.36(2H,m),2.30(4H,t,J =7.5Hz),1.70-1.48(16H,m),1.44-1.19(48H,m),1.00(6H,t,J=7.1Hz),0.92-0.81(18H,m).

[0339] MS m / z(M+H):1012.

[0340] [Example 10]

[0341] [Chemical formula 31]

[0342]

[0343] Using 2-hexyloctyl 6-hydroxyundecanoate obtained by the same method as [Example 1-2] as a raw material, 1-((2-hexyloctyl)oxy)-1-oxaundec-6-yl 1H-1,2,4-triazole-1-carboxylate (Compound [1-9]) was obtained by the same method as [Example 6].

[0344] 1 H-NMR(CDCl3)δ:8.81(1H s),8.07(1H,s),5.22-5.11(1H,m),3.95(2H,d,J=5.8Hz),2.31(2H,t,J=7.4Hz),1.88-1.51(7H,m),1.50-1.19(28H,m),0.94-0.82(9H,m).

[0345] The obtained compound [1-9] (0.38 g) was used as a raw material, and bis(2-hexyloctyl)12-(3-(diethylamino)propyl)-8,16-dioxo-6,18-dipentyl-7,9,15,17-tetraoxo-12-azatricosane dioic acid ester (compound [3-10] (0.31 g, yield 90%)) was obtained by the same method as [Example 6].

[0346] 1 H-NMR(CDCl3)δ:4.72-4.62(2H,m),4.22-4.07(4H,m),3.96

[0347] (4H,d,J=5.8Hz),2.80(4H,t,J=6.4Hz),2.60-2.45(6H,m),2.44-2.36(2H,m),2.30(4H,t,J =7.5Hz),1.69-1.46(16H,m),1.44-1.18(56H,m),1.00(6H,t,J=7.1Hz),0.94-0.80(18H,m).

[0348] MS m / z(M+H):1068.

[0349] [Comparative Example 1]

[0350] [Chemical formula 32]

[0351]

[0352] 1,1'-Carbonyldiimidazole (328 mg) was added to a solution of 2-pentylheptyl 5-hydroxyundecanoate (500 mg) in tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 30 minutes. Water (10 mL) and hexane (20 mL) were added to the reaction mixture, and the organic layer was separated and washed with water and a saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound [1-1B] (636 mg) as a light yellow oil.

[0353] 1 H-NMR(CDCl3)δ: 8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m),3.9 7(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0354] Acetonitrile (2.5 mL), compound [2-1] (564 mg) and potassium carbonate (208 mg) were added to the obtained compound [1-1B] (636 mg), and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (5 mL) was added, and after filtering out the insoluble matter, the solvent was distilled off under reduced pressure. Ethyl acetate (20 mL) and water (20 mL) were added to separate the organic layer. After washing with water and a saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain compound [3-1] (676 mg, yield 65% (2 steps)) as a colorless oil.

[0355] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97(2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2. 55-2.48(6H,m),2.35-2.27(4H,m),1.71-1.55(9H,m),1.36-1.20(36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0356] MS m / z(M+H):755.

[0357] [Comparative Example 2]

[0358] [Chemical formula 33]

[0359]

[0360] 1,1'-Carbonyldiimidazole (1.3 g) was added to a tetrahydrofuran (10 mL) solution of 2-butyloctyl 5-hydroxyundecanoate (2.0 g), and the mixture was stirred at room temperature for 1 hour. Water (10 mL) and hexane (10 mL) were added to the reaction mixture, and the organic layer was separated and washed with water and a saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound [1-2B] (3.0 g) as a light yellow oil.

[0361] 1 H-NMR(CDCl3)δ: 8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m),3.9 7(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0362] Acetonitrile (10 mL), compound [2-1] (2.2 g) and potassium carbonate (1.6 g) were added to the obtained compound [1-2B] (3.0 g), and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (20 mL) and water (20 mL) were added, the organic layer was separated, and the solvent was distilled off under reduced pressure. Ethyl acetate (10 mL), hexane (10 mL), water (10 mL) and methanol were added to the obtained residue, and the organic layer was separated. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain compound [3-2] (2.7 g, yield 66% (2 steps)) as a colorless oil.

[0363] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97(2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2. 55-2.48(6H,m),2.35-2.27(4H,m),1.71-1.55(9H,m),1.36-1.20(36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0364] MS m / z(M+H):755.

[0365] [Comparative Example 3]

[0366] [Chemical formula 34]

[0367]

[0368] 1,1'-Carbonyldiimidazole (6.6 g) was added to a solution of 2-butyloctyl 10-hydroxyhexadecanoate (12.0 g) in tetrahydrofuran (60 mL), and the mixture was stirred at room temperature for 12 hours. Water (60 mL) and hexane (60 mL) were added to the reaction mixture, and the organic layer was separated and washed with water (20 mL) and a saturated sodium chloride aqueous solution (20 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound [1-3B] (16.7 g) as a light yellow oil.

[0369] 1 H-NMR(CDCl3)δ:8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m),3.9 7(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(34H,m),0.91-0.85(9H,m).

[0370] Acetonitrile (60 mL), compound [2-1] (9.9 g) and potassium carbonate (7.9 g) were added to the obtained compound [1-3B] (16.7 g), and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (60 mL) and water (60 mL) were added, the organic layer was separated, and the solvent was distilled off under reduced pressure. Ethyl acetate (60 mL), hexane (60 mL), water (60 mL) and methanol were added to the obtained residue, and the organic layer was separated. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain compound [3-3] (11.1 g, yield 51% (2 steps)) as a colorless oil.

[0371] 1 H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.20-4.08(4H,m),3.97

[0372] (2H,d,J=5.6Hz),2.89-2.77(4H,m),2.73-2.42(8H,m),2.29(4H,t,J=7.6Hz), 1.68-1.48(9H,m),1.39-1.18(42H,m),1.10-0.98(6H,m),0.94-0.81(12H,m).

[0373] MS m / z(M+H):798.

[0374] [Comparative Example 4]

[0375] [Chemical formula 35]

[0376]

[0377] 1,1'-Carbonyldiimidazole (296 mg) was added to a solution of 2-pentylheptyl 5-hydroxyoctanoate (400 mg) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 1 hour. Water (4 mL), hexane (9 mL) and ethyl acetate (1 mL) were added to the reaction mixture, and the organic layer was separated and washed with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound [1-5B] (505 mg) as a light yellow oil.

[0378] 1 H-NMR(CDCl3)δ:8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m) ,3.97(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(18H,m),0.91-0.85

[0379] (9H,m).

[0380] Acetonitrile (2.5 mL), compound [2-3] (122 mg) and potassium carbonate (165 mg) were added to the obtained compound [1-5B] (505 mg), and stirred at 80 ° C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (8 mL) and water (4 mL) were added to separate the organic layer. After washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain compound [3-5] (304 mg, yield 56%) as a colorless oil.

[0381] 1H-NMR(CDCl3)δ: 4.74-4.67(2H,m),4.22-4.10(4H,m),3.97(4H,d,J=5.6Hz),2.83(4H,t,J=6.4Hz),2.69-2.65(2H,m),2 .55-2.49(6H,m),2.34-2.30(4H,m),1.74-1.48(14H,m),1.43-1.20(36H,m),1.01(6H,t,J=7.2Hz),0.93-0.87(18H,m).

[0382] MS m / z(M+H):914.

[0383] [Comparative Example 5]

[0384] [Chemical formula 36]

[0385]

[0386] 1,1'-Carbonyldiimidazole (0.53 g) was added to a tetrahydrofuran (4 mL) solution of 2-pentylheptyl 5-hydroxyundecanoate (0.80 g), and stirred at room temperature for 1 hour. Water (4 mL) and hexane (4 mL) were added to the reaction mixture, and the organic layer was separated and washed with a saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound [1-1B] (1.18 g) as a colorless oil.

[0387] 1 H-NMR(CDCl3)δ: 8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m),3.9 7(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m).

[0388] Acetonitrile (2.5 mL), compound [2-4] (0.12 g) and potassium carbonate (0.33 g) were added to the obtained compound [1-1B] (0.59 g), and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (3 mL) and water (3 mL) were added, the organic layer was separated, and the solvent was distilled off under reduced pressure. Ethyl acetate (3 mL), hexane (3 mL), water (3 mL) and methanol were added to the obtained residue, and the organic layer was separated. After washing with water and a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain compound [3-6] (0.26 g, yield 47%) as a colorless oil.

[0389] 1 H-NMR (CDCl3) δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J = 6.0Hz), 2.80 (4H, t, J = 6.4Hz), 2.61-2.45 (6H, m), 2. 44-2.37(2H,m),2.32(4H,t,J=7.2Hz),1.74-1.49(16H,m),1.35-1.21(48H,m),1.00(6H,t,J=7.2Hz),0.91-0.85(18H,m).

[0390] MS m / z(M+H):1012.

[0391] [Comparative Example 6]

[0392] [Chemical formula 37]

[0393]

[0394] To a mixture of 2-butyloctyl 5-hydroxyundecanoate (1.6 g), triethylamine (2.4 mL) and tetrahydrofuran (16 mL) was added 4-nitrophenyl chloroformate (1.7 g), and stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. After washing with water and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [1-2C] (2.0 g) as a colorless oil.

[0395] 1H-NMR(CDCl3)δ:8.28(2H,d,J=9.3Hz),7.39(2H,d,J=9.3Hz),4.88-4.77(1H,m),3.99(2H, d,J=6.0Hz),2.41-2.31(2H,m),1.80-1.48(7H,m),1.44-1.20(24H,m),0.92-0.83(9H,m).

[0396] Tetrahydrofuran (20 mL), compound [2-3] (2.3 g), triethylamine (1.6 mL) and 4-dimethylaminopyridine (1.4 g) were added to the obtained compound [1-2C] (2.0 g), and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. After washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain compound [3-2HY] (1.1 g) as a colorless oil.

[0397] 1 H-NMR(CDCl3)δ:4.75-4.64(1H,m),4.25-4.15(2H,m),3.97

[0398] (2H,d,J=6.0Hz),3.54(2H,t,J=5.4Hz),2.89(2H,t,J=6.6Hz),2.75-2.63(4H,m),2.60-2.42(6H,m),2 .33(2H,t,J=6.6Hz),1.73-1.50(7H,m),1.39-1.20(24H,m),1.03(6H,t,J=7.2Hz),0.95-0.81(9H,m).

[0399] To the obtained compound [3-2HY] (250 mg) were added dichloromethane (5 mL), decanoic acid (109 mg), triethylamine (0.35 mL), 4-dimethylaminopyridine (154 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg), and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain a colorless oily compound [3-2] (195 mg, yield 27% (3 steps)).

[0400] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97

[0401] (2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2.55-2.48(6H,m),2.35-2.27(4H,m),1.71-1.55(9H,m),1.36-1.20

[0402] (36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[0403] MS m / z(M+H):755.

[0404] [Comparative Example 7]

[0405] [Chemical formula 38]

[0406]

[0407] 4-Nitrophenyl chloroformate (1.0 g) was added to a mixture of 2-butyloctyl 10-hydroxyhexadecanoate (1.5 g), triethylamine (1.4 mL) and tetrahydrofuran (15 mL), and stirred at room temperature for 8 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. After washing with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain compound [1-3C] (2.1 g) as a colorless oil.

[0408] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),4.86-4.76( 1H,m),3.97(2H,d,J=5.7Hz),2.30(2H,t,J=7.2Hz),1.74-1.20(41H,m),0.92-0.85(9H,m).

[0409] Tetrahydrofuran (17 mL), compound [2-3] (1.7 g), triethylamine (1.2 mL) and 4-dimethylaminopyridine (1.0 g) were added to the obtained compound [1-3C] (1.7 g), and stirred at 80°C for 7 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the organic layer was separated. After washing with a saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain compound [3-3HY] (1.2 g) as a colorless oil.

[0410] 1 H-NMR(CDCl3)δ:4.75-4.61(1H,m),4.21(2H,t,J=6.6Hz),3.97(2H,d,J=5.7Hz),3.55(2H,t,J=5.1Hz),2.89(2H,t,J=6.6Hz),2.76- 2.65(4H,m),2.64-2.41(6H,m),2.30(2H,t,J=8.1Hz),1.72-1.45(7H,m),1.40-1.20(34H,m),1.13-0.98(6H,m),0.96-0.81(9H,m).

[0411] To the obtained compound [3-3HY] (250 mg) were added dichloromethane (5 mL), octanoic acid (81 mg), triethylamine (0.31 mL), 4-dimethylaminopyridine (136 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg), and stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain the compound [3-3] (271 mg, yield 50% (3 steps)) as a colorless oil.

[0412] 1 H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.20-4.08(4H,m),3.97(2H,d,J=5.6Hz),2.89-2.77(4H,m),2.73-2.42( 8H,m),2.29(4H,t,J=7.6Hz),1.68-1.48(9H,m),1.39-1.18(42H,m),1.10-0.98(6H,m),0.94-0.81(12H,m).

[0413] MS m / z(M+H):798.

[0414] According to the results of the embodiments and comparative examples, the production method of the present invention (synthesis method A, Examples 1 to 6), the production method described in WO2021 / 095876 (synthesis method B, Comparative Examples 1 to 5), and the production method described in WO2019 / 235635 (synthesis method C, Comparative Examples 6 to 7) and the yields of the target compounds are summarized in Table 1.

[0415] [Table 1]

[0416] Table 1: Synthesis methods and yields

[0417]

[0418] From the above results, it is understood that the target compound can be synthesized at a higher yield than the conventional method by using the production method of the present invention.

[0419] The reason for the improved yield of the present invention was investigated. Under the conditions of Comparative Example 1, the imidazole separated from the compound [1-1B] by the progress of the reaction promoted the heterogeneous reaction of the compound [2-1], thereby generating the compound [2-3] and the compound [2-3DA], and through these, multiple by-products such as the compound [3-1HY] and the compound [3-1DA] were generated, so it is believed that the yield is low. On the other hand, under the conditions of Example 1, the reactivity of the triazole separated from the compound [1-1] is lower than that of the imidazole, so the heterogeneous reaction of the compound [2-1] is very slow, and the generation of by-products is suppressed, so it is believed that the yield is high.

[0420] [Chemical formula 39]

[0421]

[0422] Compound [2-1] in the reaction solution under the reaction conditions of Comparative Example 1 was subjected to silica gel thin layer chromatography. Potassium carbonate (25 mg) was added to a mixture of compound [2-1] (100 mg) and acetonitrile (0.5 mL), and the mixture was stirred at 80°C for 2 hours, and silica gel thin layer chromatography (developing solvent: ethyl acetate / methanol 1 / 1, color developing reagent: ninhydrin) was performed. The results are shown in Figure 1 It was found that compound [2-1] did not react under the conditions of Comparative Example 1.

[0423] Compound [2-1] in the reaction solution when imidazole was added under the reaction conditions of Comparative Example 1 was subjected to silica gel thin layer chromatography. Imidazole (20 mg) was added to a mixture of compound [2-1] (100 mg), potassium carbonate (25 mg) and acetonitrile (0.5 mL), and the mixture was stirred at room temperature, 60°C or 80°C for 3 hours, and silica gel thin layer chromatography (developing solvent: ethyl acetate / methanol 1 / 1, color developing reagent: ninhydrin) was performed. The results are shown in Figure 2 It was found that compound [2-1] was converted into compound [2-3] and compound [2-3DA] under the conditions of Comparative Example 1 with the addition of imidazole at a reaction temperature of 60°C or 80°C.

[0424] In summary, under the conditions of Comparative Example 1, compound [2-1] promoted the heterogeneous reaction due to the increase in the amount of imidazole produced as the reaction proceeded, producing compound [2-3] and compound [2-3DA], and through these, a plurality of by-products were produced, so it is considered that the yield was reduced.

Claims

1. A compound or a salt thereof, which is represented by the 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 2 to 12 carbon atoms, R 3 It represents a hydrocarbon group having 6 to 22 carbon atoms.

2. The compound or salt thereof according to claim 1, wherein R 1 It represents a hydrocarbon group having 3 to 6 carbon atoms.

3. The compound or salt thereof according to claim 1 or 2, wherein R 2 It represents a divalent hydrocarbon group having 3 to 8 carbon atoms.

4. The compound or salt thereof according to claim 1 or 2, wherein R 3 It represents a hydrocarbon group having 10 to 14 carbon atoms.

5. The compound or salt thereof according to claim 1 or 2, wherein R 3 Indicates -R 31 -C(R 32 )R 33 The group represented by R 31 represents a divalent hydrocarbon group having 1 to 5 carbon atoms, R 32 and R 33 Each independently represents a hydrocarbon group having 1 to 8 carbon atoms.

6. A compound or a salt thereof represented by formula [1-1], formula [1-2], formula [1-3], formula [1-4], formula [1-5], formula [1-6], formula [1-7], formula [1-8] or formula [1-9], 7. A method for producing a compound represented by formula [3] or a salt thereof, the method comprising reacting the compound represented by formula [1] or a salt thereof according to claim 1 with a compound represented by formula [2] or a salt thereof, In the formula, R 4 and R 5 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 6 represents a divalent hydrocarbon group having 2 to 4 carbon atoms, R 7 and R 8 each independently represents a divalent hydrocarbon group having 2 to 4 carbon atoms, R 9 Represents a hydrogen atom or -COR 10 , R 10 represents a hydrocarbon group having 5 to 18 carbon atoms, In the formula, R 1 , R 2 and R 3 The definition of is the same as that in formula [1], R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that in formula [2], R 11 Indicates -COR 10 or R 10 The definition of is the same as that in formula [2], R 1 , R 2 and R 3 The definition of is the same as that in formula [1].

8. The method according to claim 7, wherein: R 4 and R 5 It represents a hydrocarbon group having 2 carbon atoms.

9. The method according to claim 7 or 8, wherein: R 6 It represents a divalent hydrocarbon group having 2 or 3 carbon atoms.

10. The method according to claim 7 or 8, wherein: R 7 and R 8 Each independently represents a divalent hydrocarbon group having 2 carbon atoms.

11. The method according to claim 7 or 8, wherein: R 9 Indicates -COR 10 , R 10 It represents a hydrocarbon group having 7 to 9 carbon atoms.

12. The method according to claim 7 or 8, which is any one of the following (a), (b), (c), (d), (e), (f), (g), (h), (i) or (j): (a) the compound represented by formula [1] or a salt thereof is the compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is the compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is the compound represented by formula [3-1] or a salt thereof; (b) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-2] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-1] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-2] or a salt thereof; (c) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-3] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-3] or a salt thereof; (d) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-4] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-2] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-4] or a salt thereof; (e) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-5] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-3] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-5] or a salt thereof; (f) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-1] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-6] or a salt thereof; (g) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-6] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-7] or a salt thereof; (h) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-7] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-8] or a salt thereof; (i) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-8] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-9] or a salt thereof; or (j) the compound represented by formula [1] or a salt thereof is a compound represented by formula [1-9] or a salt thereof, the compound represented by formula [2] or a salt thereof is a compound represented by formula [2-4] or a salt thereof, and the compound represented by formula [3] or a salt thereof is a compound represented by formula [3-10] or a salt thereof,

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