Method for producing aryl ester-containing carboxylic acid and method for producing cationic lipid

Abstract

The present invention provides: a method for producing a very pure aryl ester-containing carboxylic acid, wherein oligomer production is suppressed and a low-productivity purification step, such as column chromatography, is not required; and a method for producing a cationic lipid. The method for producing an aryl ester-containing carboxylic acid (1) comprises the following steps: 1) a step for obtaining a compound (11) by reacting a compound (7) in the presence of an aprotic solvent using potassium tert-butoxide and tert-butyl alcohol; 2) a step for obtaining a compound (12) by reacting the compound (11) and a compound (13) using a condensing agent; and 3) a step for obtaining a compound (1) (A is, e.g., phenyl having a -O-C(=O)R20 group, and B is, e.g., hydroxy group-bearing phenyl) by deprotection of the tert-butyl group in the compound (12) in an organic solvent using trifluoromethanesulfonic acid, methanesulfonic acid, a TMS-Cl + sodium iodide combination, or TMS-I.

Description

Method for producing carboxylic acid containing aryl ester and method for producing cationic lipid

[0001] The present invention relates to a method for producing carboxylic acids containing aryl esters and a method for producing cationic lipids.

[0002] Carboxylic acids containing aryl esters currently play an important role as partial structures of various acetic acid derivative pharmaceuticals, as typified by nonsteroidal anti-inflammatory drugs derived from aryl acetic acid derivatives (see Non-Patent Document 1). Furthermore, Non-Patent Document 2 shows that the high degradability of aryl esters contributes to the sustained release of lipid nanoparticles (LNPs) in mRNA therapeutic drug applications, and they also play an important role as partial structures of LNP raw materials.

[0003] On the other hand, in order to produce the above-mentioned compound containing an aryl ester, a carboxylic acid containing an aryl ester is used. When an aryl ester is to be formed using a carboxylic acid having a phenolic hydroxyl group, a method using an active acylating agent such as an acid chloride or an acid anhydride, as described in Patent Document 1, or a method using a condensing agent such as DCC or polyphosphoric acid, is considered to be desirable. However, it is known that in the method using the above-mentioned condensing agent, the condensing agent also acts on the carboxyl group of the compound containing a phenolic hydroxyl group, resulting in the production of an oligomer.

[0004] Furthermore, even when a carboxylic acid is converted into an activated acyl group using an acid anhydride or an acid chloride in advance to impart selectivity to the carbonyl group and then the phenolic hydroxyl group is reacted with, it is known that the carboxyl group contained in the phenolic hydroxyl group reacts with the activated acyl group, resulting in the formation of a hetero acid anhydride in which not only the desired aryl ester but also the carboxyl group reacts (Non-Patent Document 3). This hetero acid anhydride produces oligomers similar to those produced when a condensing agent is used, due to the reaction of the phenolic hydroxyl group.

[0005] JP 2011-105667 A International Publication No. 2019 / 188867 International Publication No. 2021 / 195529

[0006] Journal of the Japanese Society of Internal Medicine 100: 2888-2901, 2011 Adv. Funct. Mater. 30, 1910575 (2020) Chem. Papers, 1997, 51, 111-116

[0007] However, since the oligomers have similar reactivity and properties to the simple compounds, they may cause various side reactions and may be difficult to remove during purification.

[0008] For example, in the case of reacting oleic anhydride with 4-hydroxyphenylacetic acid during the synthesis of 4-oleoyloxyphenylacetic acid described in the examples of Patent Document 2, oligomers of 4-hydroxyphenylacetic acid are produced, and therefore six extractions using acetonitrile and purification using silica gel column chromatography are required, and the amount of 4-oleoyloxyphenylacetic acid obtained is small compared to the amount of oleic anhydride used, so that this is not a satisfactory level as a general production method.

[0009] Furthermore, the pKa of the phenolic hydroxyl group is 8-11, which is higher in acidity than alcohols or water. Therefore, aryl esters are generally known to be highly decomposable in water or alcohol, and are particularly prone to decomposition under basic conditions. This poses a significant problem in the production of a carboxylic acid containing a target aryl ester.

[0010] In view of the above problems, the present invention aims to provide a method for producing a highly pure aryl ester-containing carboxylic acid and a method for producing a cationic lipid, which suppress the formation of oligomers and do not require a low-productivity purification step such as column chromatography.

[0011] As a result of extensive research, the inventors have found that a hydroxyarylcarboxylic acid esterified with a methyl group or an ethyl group can be transesterified using potassium tert-butoxide to introduce a tert-butyl group only into the carboxylic acid, and then the hydroxy group is esterified and then the tert-butyl group is deprotected with a specific deprotecting agent, thereby essentially avoiding the by-production of oligomers and enabling the production of a highly pure carboxylic acid containing an aryl ester without carrying out a low-productivity purification method such as column chromatography, and have thus completed the present invention.

[0012] That is, the present invention encompasses the following: [1] A method for producing a carboxylic acid containing an aryl ester represented by the following general formula (1), comprising the following three steps: (Step 1) reacting a compound represented by the following general formula (7) using potassium tert-butoxide and tert-butyl alcohol in the presence of an aprotic solvent to obtain a compound represented by the following general formula (11), (Step 2) reacting a compound represented by the following general formula (11) with a compound represented by the following general formula (13) using a condensing agent to obtain a compound represented by the following general formula (12), (Step 3) deprotecting the tert-butyl group of the compound represented by the following general formula (12) using trifluoromethanesulfonic acid, methanesulfonic acid, a combination of trimethylsilyl chloride (TMS-Cl) and sodium iodide, or trimethylsilyl iodide (TMS-I) in an organic solvent to obtain a compound represented by the following general formula (1);

[0013]

[0014] In general formula (1), A is a group represented by the following general formula (2), (3), or (4), and n is an integer of 1 to 10 representing the number of repeating methylene group units:

[0015]

[0016] In general formula (2), R １ ~R ５ At least one selected from the following general formula (5) is a group represented by the following general formula (5), and the remaining groups are each independently a hydrogen atom, a halogen atom, or an alkyl group;６ ~R １２ At least one selected from the following general formula (5) is a group represented by the following general formula (5), and the remaining groups are each independently a hydrogen atom, a halogen atom, or an alkyl group; １３ ~R １９ at least one selected from the following is a group represented by general formula (5), and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group:

[0017]

[0018] In general formula (5), R ２０ is a structure I, II, or III shown below, where I: a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue, and II: a group represented by the following general formula (6):

[0019]

[0020] In the general formula (6), k is an integer of 2 to 10 representing the number of repeating methylene units, and R ２１ is a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue, III: a group containing a benzene ring and a guanidino group and consisting of 7 or 8 carbon atoms, 3 nitrogen atoms, and a hydrogen atom;

[0021]

[0022] In the general formula (7), B is a group represented by the following general formula (8), (9), or (10), n is an integer of 1 to 10 representing the number of repeating methylene units, and R ２２ is methyl or ethyl,

[0023]

[0024] In general formula (8), R ２３ ~R ２７ At least one selected from the following is a hydroxy group, and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group; ２８ ~R３４ At least one selected from the following is a hydroxy group, and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group; ３５ ~R ４１ at least one selected from is a hydroxy group, and the rest are each independently a hydrogen atom, a halogen atom, or an alkyl group;

[0025]

[0026] In the general formula (11), B is a group represented by the general formula (8), (9), or (10), and n is an integer of 1 to 10 representing the number of repeating methylene groups;

[0027]

[0028] In general formula (13), R ２０ is structure I, II, or III shown above;

[0029]

[0030] In the general formula (12), A is a group represented by the general formula (2), (3), or (4), and n is an integer of 1 to 10 representing the number of repeating methylene groups.

[0031] [2] The method according to [1], wherein A in the general formulas (1) and (12) is a group represented by the general formula (2), and B in the general formulas (7) and (11) is a group represented by the general formula (8).

[0032] [3] In the general formula (2), R １ ~R ５ At least one selected from the group represented by the general formula (5) is a group represented by the general formula (5), and the remaining groups are each independently a hydrogen atom. ２３ ~R ２７ At least one selected from the group consisting of hydroxyl groups and the remaining groups each independently being a hydrogen atom.

[0033] [4] In the general formula (2), R ３ is a group represented by the general formula (5), and R １ , R ２ , R４ , and R ５ are each independently a hydrogen atom, and in the general formula (8), R ２５ is a hydroxy group, and R ２３ , R ２４ , R ２６ , and R ２７ and each independently represents a hydrogen atom.

[0034] [5] R in the general formulas (5) and (13) ２０ [1] to [4], wherein the structure is the structure I or II.

[0035] [6] The method according to any one of [1] to [5], wherein n is 1.

[0036] [7] The method according to any one of [1] to [6], wherein methanesulfonic acid is used in the step 3.

[0037] [8] The method according to any one of [1] to [7], wherein the aprotic solvent described in (Step 1) is toluene.

[0038] [9] The method according to any one of [1] to [8], wherein the condensing agent described in (Step 2) is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), and N,N'-diisopropylcarbodiimide (DIC).

[0039]

[10] The method according to any one of [1] to [9], wherein the organic solvent described in (Step 3) above is acetonitrile, dichloromethane, chloroform, or a mixture thereof.

[0040]

[11] In the general formula (7), R ２２

[11] The method according to any one of [1] to

[10] , wherein

[0041]

[12] A method for producing a cationic lipid, comprising (Step 1), (Step 2), and (Step 3) according to any one of [1] to

[11] , and (Step 4) a step of condensing the obtained carboxylic acid containing an aryl ester represented by general formula (1) with a compound having a disulfide bond, at least one tertiary nitrogen, and at least one hydroxyl group or amino group.

[0042]

[13] The compound is a compound represented by general formula (14), and in the step 4, the aryl ester-containing carboxylic acid and a hydroxy group of the compound are condensed to obtain a cationic lipid represented by general formula (20), according to the method for producing a cationic lipid according to

[12] :

[0043]

[0044] In general formula (14), R ４２ and R ４２ａ each independently represents an alkylene group having 1 to 6 carbon atoms; ４３ and R ４３ａ each independently represents a non-cyclic alkyl tertiary amino group having 1 to 6 carbon atoms and one tertiary amino group, or a cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and one or two tertiary amino groups; R ４４ and R ４４ａ each independently represents an alkylene group or an oxydialkylene group having 8 or less carbon atoms;

[0045]

[0046] In formula (20), each symbol has the same meaning as defined above.

[0047] The production method of the present invention can essentially avoid the by-production of oligomers. Furthermore, it can suppress the decomposition of aryl esters and provide carboxylic acids containing high-purity aryl esters without the need for low-productivity purification steps such as column chromatography. Therefore, it can also be used as a method for producing raw materials in the pharmaceutical field, where high-purity products are particularly required. Furthermore, in the synthesis of cationic lipids using carboxylic acids containing aryl esters as raw materials, as shown in Patent Document 2, it is possible to synthesize them while essentially avoiding the production of impurities derived from oligomers.

[0048] Hereinafter, embodiments of the present invention will be described, but the present invention is not limited thereto. In the following embodiments, a method for producing a carboxylic acid containing an aryl ester and a method for producing a cationic lipid will be described.

[0049] [Method for producing carboxylic acid containing aryl ester] The present invention relates to a method for producing a carboxylic acid containing an aryl ester represented by general formula (1), which includes steps 1 to 3. In general formulas (1) and (12), A represents a group represented by general formula (2), (3), or (4), and preferably represents a group represented by general formula (2). In general formulas (1) and (12), n represents the number of repeating methylene group units and is an integer of 1 to 10, preferably an integer of 1 to 5, and more preferably 1.

[0050] In general formula (2), R １ ~R ５ At least one selected from the group consisting of R １ ~R ５ One selected from the group represented by general formula (5) is a group represented by general formula (2). １ ~R ５ In the formula (5), the remaining substituents other than the group represented by formula (5) are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom.

[0051] In general formula (3), R ６ ~R １２ At least one selected from the group consisting of R ６~R １２ One selected from the group represented by general formula (5) is a group represented by general formula (3). ６ ~R １２ In the formula (5), the remaining substituents other than the group represented by formula (5) are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom.

[0052] In general formula (4), R １３ ~R １９ At least one selected from the group consisting of R １３ ~R １９ One selected from the group represented by general formula (4) is a group represented by general formula (5). １３ ~R １９ In the formula (5), the remaining substituents other than the group represented by formula (5) are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom.

[0053] In the present invention, the "alkyl group" may be linear or branched. The number of carbon atoms in the alkyl group is preferably 1 to 6, and more preferably 1 to 4. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1,2-dimethylpropyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 2,2-dimethylbutyl group, and a 2,3-dimethylbutyl group, and preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.

[0054] In general formulas (5) and (13), R ２０ is structure I, II, or III shown above, preferably structure I or II, and most preferably structure I.

[0055] The structure of I is a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue. The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated.

[0056] R in general formulas (5) and (13) ２０ is a linear aliphatic hydrocarbon group described in I, ２０ has 12 to 22 carbon atoms, preferably 12 to 20, and more preferably 14 to 20. Specific examples include dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, icosyl group, henicosyl group, docosyl group, dodecenyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, hexadecenyl group, heptadecenyl group, octadecenyl group, nonadecenyl group, icosenyl group, henicosyl group, docosenyl group, dodecadienyl group, and Examples of such groups include a methyl group, a tridecadienyl group, a tetradecadienyl group, a pentadecadienyl group, a hexadecadienyl group, a heptadecadienyl group, an octadecadienyl group, a nonadecadienyl group, an icosadienyl group, a henicosadienyl group, a heneicosadienyl group, a docosadienyl group, an octadecatrienyl group, an icosatrienyl group, an icosatetraenyl group, an icosapentaenyl group, and a docosahexaenyl group.

[0057] R in general formulas (5) and (13) ２０ is a branched aliphatic hydrocarbon group described in I, ２０ has 12 to 37 carbon atoms, preferably 14 to 37. Specific examples include an isostearyl group, a 1-hexylheptyl group, a 1-hexylnonyl group, a 1-octylnonyl group, a 1-octylundecyl group, a 1-decylundecyl group, a 1-dodecyltridecyl group, a 1-tetradecylpentadecyl group, a 1-hexadecylheptadecyl group, and a 1-octadecylnonadecyl group, and are preferably a 1-hexylheptyl group, a 1-hexylnonyl group, a 1-octylnonyl group, a 1-octylundecyl group, a 1-decylundecyl group, a 1-dodecyltridecyl group, a 1-tetradecylpentadecyl group, or a 1-hexadecylheptadecyl group.

[0058] R in general formulas (5) and (13) ２０ When the aliphatic hydrocarbon group is I and the aliphatic hydrocarbon group is unsaturated, the number of carbon atoms in the aliphatic hydrocarbon group is 12 to 22, preferably 12 to 20, and more preferably 14 to 20. The number of unsaturated bonds contained in the aliphatic hydrocarbon group is usually 1 to 6, preferably 1 to 3, and more preferably 1. Unsaturated bonds include carbon-carbon double bonds and carbon-carbon triple bonds, with carbon-carbon double bonds being preferred. Specific examples of the aliphatic hydrocarbon group having 12 to 22 carbon atoms and an unsaturated bond include dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, nonadecadienyl, icosadienyl, henicosadienyl, docosadienyl, octadecatrienyl, icosatrienyl, icosatetraenyl, icosapentaenyl, and docosahexaenyl groups.

[0059] In the present invention, examples of the fat-soluble vitamin residue include residues derived from fat-soluble vitamins, and residues in which a hydroxyl group, which is a functional group in a fat-soluble vitamin, is converted to another reactive functional group. Examples include monovalent groups having a structure obtained by removing a hydroxyl group from a fat-soluble vitamin, and monovalent groups having a structure obtained by removing a hydrogen atom from a hydroxyl group of a fat-soluble vitamin. Examples of fat-soluble vitamins include retinol, ergosterol, 7-dehydrocholesterol, calciferol, corcalciferol, dihydroergocalciferol, dihydrotachysterol, tocopherol, and tocotrienol, with tocopherol being preferred.

[0060] In the present invention, examples of the sterol derivative residue include residues derived from sterol derivatives, and residues in which a hydroxyl group, which is a functional group in a sterol derivative, has been converted to another reactive functional group. Examples include a monovalent group having a structure obtained by removing a hydroxyl group from a sterol derivative, or a monovalent group having a structure obtained by removing a hydrogen atom from a hydroxyl group of a sterol derivative. Examples of the sterol derivative include cholesterol, cholestanol, stigmasterol, β-sitosterol, lanosterol, and ergosterol, with cholesterol or cholestanol being preferred.

[0061] R in general formulas (5) and (13) ２０ When I is a fat-soluble vitamin residue, examples include monovalent groups having a structure obtained by removing a hydroxy group from a fat-soluble vitamin. Specific examples of fat-soluble vitamins include retinol, ergosterol, 7-dehydrocholesterol, calciferol, corcalciferol, dihydroergocalciferol, dihydrotachysterol, tocopherol, and tocotrienol, with tocopherol being preferred.

[0062] R in general formulas (5) and (13) ２０ When is I and is a sterol derivative residue, examples include monovalent groups having a structure obtained by removing a hydroxy group from a sterol derivative. Specific examples of the sterol derivative include cholesterol, cholestanol, stigmasterol, β-sitosterol, lanosterol, and ergosterol, and preferably cholesterol or cholestanol.

[0063] The structure of II is a group represented by the general formula (6) above, and k is an integer of 2 to 10, preferably 2 to 7, representing the number of repeating methylene units.

[0064] R in general formula (6) ２１is a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue. The aliphatic hydrocarbon group may be linear or branched, and may be saturated or unsaturated.

[0065] R in general formula (6) ２１ When R is a straight-chain aliphatic hydrocarbon group, ２１ has 12 to 22 carbon atoms, preferably 12 to 20, and more preferably 14 to 20. Specific examples include dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, icosyl group, henicosyl group, docosyl group, dodecenyl group, tridecenyl group, tetradecenyl group, pentadecenyl group, hexadecenyl group, heptadecenyl group, octadecenyl group, nonadecenyl group, icosenyl group, henicosyl group, docosenyl group, dodecadienyl group, and Examples of such groups include a methyl group, a tridecadienyl group, a tetradecadienyl group, a pentadecadienyl group, a hexadecadienyl group, a heptadecadienyl group, an octadecadienyl group, a nonadecadienyl group, an icosadienyl group, a henicosadienyl group, a heneicosadienyl group, a docosadienyl group, an octadecatrienyl group, an icosatrienyl group, an icosatetraenyl group, an icosapentaenyl group, and a docosahexaenyl group.

[0066] R in general formula (6) ２１ When R is a branched aliphatic hydrocarbon group, ２１ has 12 to 37 carbon atoms, preferably 14 to 37. Specific examples include an isostearyl group, a 1-hexylheptyl group, a 1-hexylnonyl group, a 1-octylnonyl group, a 1-octylundecyl group, a 1-decylundecyl group, a 1-dodecyltridecyl group, a 1-tetradecylpentadecyl group, a 1-hexadecylheptadecyl group, and a 1-octadecylnonadecyl group, and particularly preferred are a 1-hexylheptyl group, a 1-hexylnonyl group, a 1-octylnonyl group, a 1-octylundecyl group, a 1-decylundecyl group, a 1-dodecyltridecyl group, a 1-tetradecylpentadecyl group, and a 1-hexadecylheptadecyl group.

[0067] R in general formula (6)２１ When is an unsaturated aliphatic hydrocarbon group, the number of carbon atoms in the aliphatic hydrocarbon group is 12 to 22, preferably 12 to 20, and more preferably 14 to 20. The number of unsaturated bonds contained in the aliphatic hydrocarbon group is usually 1 to 6, preferably 1 to 3, and more preferably 1. Unsaturated bonds include carbon-carbon double bonds and carbon-carbon triple bonds, with carbon-carbon double bonds being preferred. Specific examples of the aliphatic hydrocarbon group having 12 to 22 carbon atoms and an unsaturated bond include dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, dodecadienyl, tridecadienyl, tetradecadienyl, pentadecadienyl, hexadecadienyl, heptadecadienyl, octadecadienyl, nonadecadienyl, icosadienyl, henicosadienyl, docosadienyl, octadecatrienyl, icosatrienyl, icosatetraenyl, icosapentaenyl, and docosahexaenyl groups.

[0068] R in general formula (6) ２１ When is a fat-soluble vitamin residue, examples thereof include monovalent groups having a structure obtained by removing a hydroxy group from a fat-soluble vitamin. Specific examples of fat-soluble vitamins include retinol, ergosterol, 7-dehydrocholesterol, calciferol, corcalciferol, dihydroergocalciferol, dihydrotachysterol, tocopherol, and tocotrienol, with tocopherol being preferred.

[0069] R in general formula (6) ２１ When is a sterol derivative residue, examples thereof include monovalent groups having a structure obtained by removing a hydroxy group from a sterol derivative. Specific examples of the sterol derivative include cholesterol, cholestanol, stigmasterol, β-sitosterol, lanosterol, and ergosterol, and preferably cholesterol or cholestanol.

[0070] Structure III is a group containing a benzene ring and a guanidino group, and consisting of 7 or 8 carbon atoms, 3 nitrogen atoms, and hydrogen atoms, preferably a group containing a benzene ring and a guanidino group, and consisting of 7 carbon atoms, 3 nitrogen atoms, and hydrogen atoms. Here, the number of carbon atoms refers to the total number of the entire group, including the number of carbon atoms in the benzene ring and the guanidino group. The number of nitrogen atoms refers to the number of nitrogen atoms in the guanidino group. Structure III is more preferably a phenyl group substituted with a guanidino group.

[0071] In the general formulas (7) and (11), B is a group represented by the general formula (8), (9), or (10), and preferably a group represented by the general formula (8). ２２ is methyl or ethyl, preferably methyl. In formulas (7) and (11), n ​​represents the number of repeating methylene units and is an integer of 1 to 10, preferably an integer of 1 to 5, and more preferably 1.

[0072] In general formula (8), R ２３ ~R ２７ At least one selected from R ２３ ~R ２７ One selected from the group consisting of R in general formula (8) is a hydroxy group. ２３ ~R ２７ In the general formula (8), the remaining substituents other than the hydroxy group are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom. ２５ is a hydroxy group, and R ２３ , R ２４ , R ２６ , and R ２７ are each independently a hydrogen atom.

[0073] In general formula (9), R ２８ ~R ３４ At least one selected from R ２８ ~R ３４ One selected from the group consisting of R in general formula (9) is a hydroxy group. ２８ ~R ３４In the formula, the remaining substituents other than the hydroxy group are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom.

[0074] In general formula (10), R ３５ ~R ４１ At least one selected from R ３５ ~R ４１ One selected from the group consisting of R in general formula (10) is a hydroxy group. ３５ ~R ４１ In the formula, the remaining substituents other than the hydroxy group are each independently a hydrogen atom, a halogen atom, or an alkyl group, and preferably a hydrogen atom.

[0075] (Step 1) Step 1 is a step in which a compound represented by general formula (7) is reacted with potassium tert-butoxide and tert-butyl alcohol in the presence of an aprotic solvent to obtain a compound represented by general formula (11).

[0076] If the amount of potassium tert-butoxide used in Step 1 is too large, stirring becomes difficult, whereas if the amount is too small, the reaction does not proceed. Therefore, the amount of potassium tert-butoxide used is preferably 1.0 to 5.0 equivalents, more preferably 1.5 to 4.0 equivalents, relative to the compound represented by general formula (7).

[0077] If the amount of tert-butyl alcohol used in step 1 is too large, the reaction system becomes diluted and the reaction does not proceed, whereas if the amount is too small, stirring becomes difficult. Therefore, the amount of tert-butyl alcohol used is preferably 5 to 20 times by weight, more preferably 7 to 10 times by weight, relative to the compound represented by general formula (7).

[0078] The aprotic solvent used in step 1 is used for the purpose of preventing solidification of tert-butyl alcohol, and therefore must be compatible with tert-butyl alcohol, have a melting point of 0° C. or lower, and be non-reactive. Specifically, benzene and toluene are preferred, and toluene is more preferred.

[0079] If the amount of the aprotic solvent used in step 1 is too large, the reaction system becomes diluted and the reaction does not proceed, whereas if the amount is too small, the tert-butyl alcohol solidifies and stirring becomes difficult. Therefore, the amount of the aprotic solvent used is preferably 1 to 10 times by weight, more preferably 1 to 2 times by weight, relative to the compound represented by general formula (7).

[0080] The reaction temperature in step 1 is not particularly limited as long as the reaction system does not solidify and can be controlled to a temperature below the boiling point of the reaction solvent, but is preferably 0 to 80° C., more preferably 10 to 60° C. The reaction time is not particularly limited, but is preferably 1 to 72 hours, more preferably 1 to 24 hours.

[0081] After the reaction in step 1, the product can be purified by a commonly known technique without the need for a purification step with low productivity such as column chromatography, such as washing with water to remove hydrophilic impurities, adsorption purification using an ion exchange resin, or concentration to remove the solvent.

[0082] (Step 2) Step 2 is a step of reacting a compound represented by general formula (11) with a compound represented by general formula (13) using a condensing agent to obtain a compound represented by general formula (12).

[0083] The condensing agent used in step 2 is not limited as long as it is a reagent used in a typical esterification reaction, but a carbodiimide condensing agent that can react under mild conditions is preferred. Specifically, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC hydrochloride; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The condensing agent used in step 2 is preferably selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC; N,N'-Dicyclohexylcarbodiimide), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), N,N'-dicyclohexylcarbodiimide (DCC; N,N'-Dicyclohexylcarbodiimide), and N,N'-diisopropylcarbodiimide (DIC; N,N'-diisopropylcarbodiimide), and more preferably EDC hydrochloride. The amount of the condensing agent used in step 2 is preferably 0.9 to 3.0 equivalents, more preferably 1.0 to 2.0 equivalents, relative to the hydroxy groups of the compound represented by general formula (11). In addition, 4-dimethylaminopyridine (DMAP), triethylamine, triisopropylamine, tributylamine, etc. can be added as an additive in the reaction of step 2. The amount of the additive used is preferably 0.1 to 0.5 equivalents, more preferably 0.1 to 0.3 equivalents, relative to the hydroxy group of the compound represented by general formula (11).

[0084] The solvent used in step 2 is not particularly limited as long as it is an aprotic solvent in which the raw materials can be dissolved. Specific examples include chloroform, dichloromethane, ethyl acetate, and toluene, with chloroform and dichloromethane being preferred. The amount of the solvent used in step 2 is preferably 3 to 50 times by weight, more preferably 5 to 20 times by weight, relative to the compound represented by general formula (11).

[0085] The reaction temperature in step 2 is not particularly limited, but is preferably 0 to 80° C., more preferably 10 to 30° C. The reaction time is not particularly limited, but is preferably 1 to 72 hours, more preferably 1 to 24 hours.

[0086] After the reaction in step 2, the product can be purified by a commonly known technique without the need for a purification step with low productivity such as column chromatography, specifically by washing with water to remove hydrophilic impurities, adsorption purification using an ion exchange resin or the like, or concentration to remove the solvent.

[0087] (Step 3) Step 3 is a step in which the tert-butyl group of the compound represented by general formula (12) is deprotected using trifluoromethanesulfonic acid, methanesulfonic acid, a combination of trimethylsilyl chloride (TMS-Cl) and sodium iodide, or trimethylsilyl iodide (TMS-I) in an organic solvent to obtain a compound represented by general formula (1).

[0088] The organic solvent used in step 3 is not particularly limited as long as it dissolves the compound represented by general formula (12) and can be easily distilled off under reduced pressure. Specifically, acetonitrile, dichloromethane, chloroform, etc. can be used, and a single solvent or a mixture of two or more solvents can be used.

[0089] The amount of organic solvent used in step 3 is preferably 2 to 30 times by weight, more preferably 5 to 20 times by weight, relative to that of the compound of general formula (12). If the amount of organic solvent is too large, the reaction system becomes diluted and the reaction does not proceed, whereas if the amount is too small, the aryl ester may be decomposed by the reagent.

[0090] In step 3, the tert-butyl group of the compound represented by general formula (12) is deprotected using any one of trifluoromethanesulfonic acid, methanesulfonic acid, a combination of TMS-Cl and sodium iodide, or TMS-I.

[0091] R in general formula (5) ２０ is I and the aliphatic hydrocarbon group is saturated, or R ２０ is II, and R of general formula (6) ２１ When the aliphatic hydrocarbon group is saturated, any of trifluoromethanesulfonic acid, methanesulfonic acid, a combination of TMS-Cl and sodium iodide, and TMS-I may be used.

[0092] R in general formula (5) ２０ is I and the aliphatic hydrocarbon group is unsaturated, or R ２０ is II, and R of general formula (6) ２１ If the aliphatic hydrocarbon group is unsaturated, the combination of TMS-Cl and sodium iodide or TMS-I cannot be used because they react with the unsaturated bond. Therefore, either trifluoromethanesulfonic acid or methanesulfonic acid is used.

[0093] The amount of trifluoromethanesulfonic acid, methanesulfonic acid, a combination of TMS-Cl and sodium iodide, or TMS-I used in step 3 is preferably 0.5 to 6 equivalents, more preferably 1 to 4 equivalents, relative to the amount of the compound of general formula (12). If the amount of the reagent is too small, the reaction will not proceed, whereas if the amount is too large, the aryl ester may be decomposed by the reagent.

[0094] The reaction temperature in Step 3 is preferably 10 to 40°C, more preferably 20 to 30°C. If the temperature is too low, the reaction will not proceed, whereas if the temperature is too high, the aryl ester may decompose. The reaction time is not particularly limited, but is preferably 1 to 72 hours, more preferably 1 to 24 hours.

[0095] After the reaction in step 3, the product can be purified by a commonly known technique, such as washing with water to remove hydrophilic impurities, adsorption purification using an ion exchange resin or the like, purification using crystallization, or concentration to remove the solvent.

[0096] The compounds represented by the general formula (7) and the general formula (13) used in the production method of the present invention are commercially available or can be produced according to a method known per se.

[0097] [Method for Producing Cationic Lipids] Next, a method for producing cationic lipids will be described. The method for producing cationic lipids of the present invention comprises (Step 1), (Step 2), and (Step 3) in the above-described method for producing a carboxylic acid containing an aryl ester, and (Step 4) a step of condensing the obtained carboxylic acid containing an aryl ester represented by general formula (1) with a compound having a disulfide bond, at least one tertiary nitrogen, and at least one hydroxy group or amino group. The number of tertiary nitrogens is preferably 1 to 4, more preferably 1 or 2. The number of hydroxy groups or amino groups is preferably 1 to 3, more preferably 1 or 2. The compound used in Step 4 is preferably a compound represented by the following general formula (14):

[0098]

[0099] In general formula (14), R ４２ and R ４２ａ are each independently an alkylene group having 1 to 6 carbon atoms, which may be linear or branched, but is preferably linear. The number of carbon atoms in the alkylene group is preferably 1 to 4, and more preferably 1 to 2. Specific examples of alkylene groups having 1 to 6 carbon atoms include methylene, ethylene, trimethylene, isopropylene, tetramethylene, isobutylene, pentamethylene, and neopentylene. R ４２ and R ４２ａ are preferably each independently a methylene group, an ethylene group, a trimethylene group, an isopropylene group, or a tetramethylene group, and most preferably each is an ethylene group. ４２ is R ４２ａ may be the same as or different from, but preferably, R ４２ is R ４２ａ is the same group as

[0100] R ４３ and R ４３ａeach independently represents a non-cyclic alkyl tertiary amino group having 1 to 6 carbon atoms and one tertiary amino group, or a cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and one or two tertiary amino groups, and preferably each independently represents a cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and one or two tertiary amino groups.

[0101] The alkyl group having 1 to 6 carbon atoms in the acyclic alkyl tertiary amino group having 1 to 6 carbon atoms and one tertiary amino group may be linear, branched, or cyclic. The number of carbon atoms in the alkyl group is preferably 1 to 3. Specific examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, a 1,2-dimethylpropyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, and a cyclohexyl group. A methyl group, an ethyl group, a propyl group, or an isopropyl group is preferred, and a methyl group is most preferred.

[0102] A preferred specific structure of the non-cyclic alkyl tertiary amino group having 1 to 6 carbon atoms and one tertiary amino group is １ It is shown as follows.

[0103]

[0104] C １ R ４９represents an alkyl group having 1 to 6 carbon atoms, which may be linear, branched, or cyclic. The number of carbon atoms in the alkyl group is preferably 1 to 3. Specific examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, a 1,2-dimethylpropyl group, a 2-methylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, and a cyclohexyl group. A methyl group, an ethyl group, a propyl group, or an isopropyl group is preferred, and a methyl group is most preferred.

[0105] The number of carbon atoms in the cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and 1 or 2 tertiary amino groups is preferably 4 or 5. Specific examples of the cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and 1 or 2 tertiary amino groups include an aziridylene group, an azetidylene group, a pyrrolidine group, a piperidylene group, an imidazolidylene group, and a piperaziylene group, preferably a pyrrolidine group, a piperidylene group, and a piperaziylene group, and most preferably a piperidylene group.

[0106] A preferred specific structure of the cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and one tertiary amino group is C ２ It is shown as follows.

[0107]

[0108] C ２ In the formula, r is 1 or 2. When r is 1, C ２ is a pyrrolidine group, and when r is 2, C ２ is a piperidylene group.

[0109] A preferred specific structure of the cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and two tertiary amino groups is C ３ It is shown as follows.

[0110]

[0111] C ３In the formula, s is 1 or 2. When s is 1, C ３ is an imidazolidylene group, and when s is 2, C ３ is a piperazylene group.

[0112] R ４３ is R ４３ａ may be the same as or different from, but preferably, R ４３ is R ４３ａ is the same group as

[0113] R ４４ and R ４４ａ each independently represents an alkylene group or an oxydialkylene group having 8 or less carbon atoms, and preferably each independently represents an alkylene group having 8 or less carbon atoms.

[0114] R ４４ and R ４４ａ The alkylene group having 8 or less carbon atoms, represented by the formula (I), may be linear or branched, but is preferably linear. The number of carbon atoms contained in the alkylene group is preferably 6 or less, and most preferably 4 or less. Specific examples of the alkylene group having 8 or less carbon atoms include a methylene group, an ethylene group, a propylene group, an isopropylene group, a tetramethylene group, an isobutylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, and an octamethylene group, of which a methylene group, an ethylene group, a propylene group, and a tetramethylene group are preferred, and an ethylene group is most preferred.

[0115] R ４４ and R ４４ａ An oxydialkylene group having 8 or less carbon atoms, represented by the formula (I), refers to an alkylene group (alkylene-O-alkylene) via an ether bond, and the total number of carbon atoms in the two alkylene groups is 8 or less. Here, the two alkylene groups may be the same or different, but are preferably the same. Specific examples of oxydialkylene groups having 8 or less carbon atoms include an oxydimethylene group, an oxydiethylene group, an oxydipropylene group, and an oxydibutylene group. Preferred are an oxydimethylene group, an oxydiethylene group, and an oxydipropylene group, and most preferred is an oxydiethylene group.

[0116] R ４４ is R ４４ａ may be the same as or different from, but preferably, R ４４ is R ４４ａ is the same group as

[0117] When the compound having a disulfide bond, at least one tertiary nitrogen, and at least one hydroxyl group or amino group used in step 4 is a compound represented by general formula (14), the cationic lipid is a compound represented by general formula (20).

[0118]

[0119] In formula (20), each symbol has the same meaning as defined above.

[0120] Specific examples of cationic lipids include the following: O-Ph-P3C1, O-Ph-P4C1, O-Ph-P4C2, O-Bn-P4C2, E-Ph-P4C2, L-Ph-P4C2, HD-Ph-P4C2, O-Ph-amide-P4C2, and O-Ph-C3M.

[0121]

[0122]

[0123] Step 4 is a step of condensing a carboxylic acid containing an aryl ester represented by general formula (1) with a compound having a disulfide bond, at least one tertiary nitrogen, and at least one hydroxy group or amino group. In a preferred embodiment, step 4 is a step of condensing a carboxylic acid containing an aryl ester represented by general formula (1) with a hydroxy group of a compound represented by general formula (14) described above. There are no limitations on the condensation reaction used in step 4 as long as a commonly known technique is used, but it is preferable to carry out the reaction using a condensing agent.

[0124] The condensing agent used in step 4 is not limited as long as it is a reagent used in a typical esterification reaction, but a carbodiimide condensing agent that can react under mild conditions is preferred. Specifically, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC hydrochloride; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The condensing agent used in step 4 is preferably selected from the group consisting of N,N'-dicyclohexylcarbodiimide (DCC; N,N'-Dicyclohexylcarbodiimide), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), N,N'-dicyclohexylcarbodiimide (DCC; N,N'-Dicyclohexylcarbodiimide), and N,N'-diisopropylcarbodiimide (DIC; N,N'-diisopropylcarbodiimide), and more preferably EDC hydrochloride or EDC. The amount of the condensing agent used in step 4 is preferably 0.9 to 3.0 equivalents, more preferably 1.0 to 2.0 equivalents, relative to the hydroxy groups of the compound represented by general formula (14). In addition, 4-dimethylaminopyridine (DMAP), triethylamine, triisopropylamine, tributylamine, etc. can be added as an additive in the reaction of step 4. The amount of the additive used is preferably 0.1 to 0.5 equivalents, more preferably 0.1 to 0.3 equivalents, relative to the hydroxy group of the compound represented by general formula (14).

[0125] The solvent used in step 4 is not particularly limited as long as it is an aprotic solvent in which the raw materials can be dissolved. Specific examples include chloroform, dichloromethane, ethyl acetate, and toluene, with chloroform and dichloromethane being preferred. The amount of the solvent used in step 4 is preferably 3 to 50 times by weight, more preferably 5 to 40 times by weight, relative to the compound represented by general formula (14).

[0126] The reaction temperature in step 4 is not particularly limited, but is preferably 0 to 80° C., more preferably 10 to 30° C. The reaction time is not particularly limited, but is preferably 1 to 72 hours, more preferably 1 to 24 hours.

[0127] After the reaction in step 4, the reaction product can be purified by a commonly known technique, such as washing with water to remove hydrophilic impurities, adsorption purification using an ion exchange resin, or concentration to remove the solvent.

[0128] The compound represented by general formula (14) used in step 4 can be produced by known methods (for example, the methods described in US 2014 / 0335157 A1 and WO 2016 / 121942 A1).

[0129] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. In the examples, "room temperature" generally means about 10 to 30°C, but is not strictly limited thereto.

[0130] Example 1 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate 1600 g of tert-butyl alcohol and 400 g of toluene were added to 338 g (3.01 mol) of potassium tert-butoxide (Kanto Chemical Co., Ltd.) and dissolved. A solution of 250 g (1.50 mol) of methyl 4-hydroxyphenylacetate (Tokyo Chemical Industry Co., Ltd.) dissolved in 400 g of tert-butyl alcohol and 100 g of toluene was added thereto, and the reaction was carried out at room temperature for 16 hours. The reaction solution was neutralized by adding a solution prepared by diluting 400 g of phosphoric acid in 1000 g of methanol, and the precipitated salt was filtered off, and the filtrate was concentrated using an evaporator. 1313 g of a 5% aqueous solution of sodium bicarbonate was added to the concentrate, and extraction was carried out twice using 1250 g of dichloromethane. The dichloromethane layers obtained by the two extractions were collected and mixed, and then 50 g of magnesium oxide / aluminum oxide adsorbent KW-2000 (Kyowa Chemical Industry Co., Ltd.) was added and stirred at room temperature for 30 minutes. The KW-2000 was filtered off, and the resulting solution was concentrated using an evaporator. 750 g of toluene was added to the concentrate and the mixture was concentrated again using an evaporator. This procedure was repeated twice, and the resulting crystals were vacuum-dried to obtain 225 g of tert-butyl 4-hydroxyphenylacetate (yield 72 mol% / methyl 4-hydroxyphenylacetate).

[0131] 4-hydroxyphenylacetic acid-tert-butyl １H-NMR spectrum (600 MHz, CD ３ OD) δ1.42 (s, 9H), δ3.40 (s, 2H), δ4.85 (s, 1H), δ6.70-6.73 (d, 2H), δ6.70-7.06 (d, 2H)

[0132] Step 2: Synthesis of 4-oleoyloxyphenylacetate-tert-butyl 4-hydroxyphenylacetate-tert-butyl 225 g (1.08 mol) was dissolved in 2250 g of chloroform, followed by the addition of 299 g (1.06 mol) of oleic acid (NOF Corporation), 26 g (0.22 mol) of DMAP (Koei Chemical Co., Ltd.), and 269 g (1.40 mol) of EDC hydrochloride (Tokyo Chemical Industry Co., Ltd.), and the reaction was carried out at room temperature for 1 hour. The reaction solution was washed once with 2250 g of 0.1 mol / L hydrochloric acid, once with 2250 g of 5% aqueous sodium bicarbonate solution, and once with 2250 g of ion-exchanged water, and then concentrated using an evaporator. 2250 g of hexane was added to the concentrate, and 45 g of silica gel PSQ100B (Fuji Silysia Chemical Ltd.) was added and stirred at room temperature for 30 minutes. After filtering off PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried in vacuo to obtain 486 g of tert-butyl 4-oleoyloxyphenylacetate (yield: 95 mol % / tert-butyl 4-hydroxyphenylacetate).

[0133] 4-oleoyloxyphenylacetic acid-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.87-0.89 (t, 3H), δ1.20-1.57 (m, 29H), δ1.72-1.77 (m, 2H), δ2.00-2.10 (m, 4H), δ2.52 -2.55 (t, 2H), δ3.50 (s, 2H), δ5.30-5.40 (m, 2H), δ7.02-7.30 (d, 2H), δ7.26-7.28 (d, 2H)

[0134] Step 3: Synthesis of 4-oleoyloxyphenylacetic acid 298 g (0.63 mol) of tert-butyl 4-oleoyloxyphenylacetate was dissolved in 1192 g of acetonitrile and 1192 g of chloroform, and then a solution of 96.9 g (1.01 mol) of methanesulfonic acid diluted in 298 g of acetonitrile and 298 g of chloroform was added and reacted at room temperature for 2 hours. The solution after the reaction was washed three times with 1490 g of ion-exchanged water and then concentrated using an evaporator. The concentrated crude product was recrystallized using 894 g of hexane, and the crystals were collected to obtain 159 g of 4-oleoyloxyphenylacetic acid (yield 61 mol% / tert-butyl 4-oleoyloxyphenylacetate) (yield: 59 mol% / oleic acid).

[0135] 4-oleoyloxyphenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.89-0.91 (t, 3H), δ1.20-1.57 (m, 20H), δ1.72-1.85 (m, 2H), δ2.00-2.10 (m, 4H), δ2.52 -2.70 (t, 2H), δ3.66 (s, 2H), δ5.30-5.40 (m, 2H), δ7.02-7.30 (d, 2H), δ7.28-7.32 (d, 2H)

[0136] Example 2 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate The title compound was synthesized by the method described in Step 1 of Example 1.

[0137] Step 2: Synthesis of tert-butyl 4-(2-hexadecyl octadecanoyloxy)phenylacetate 1.3 g (6.2 mmol) of tert-butyl 4-hydroxyphenylacetate was dissolved in 13.2 g of chloroform, and then 3.0 g (5.9 mmol) of 2-hexadecyl octadecanoic acid (Tokyo Chemical Industry Co., Ltd.), 148 mg (1.3 mmol) of DMAP (Koei Chemical Co., Ltd.), and 1.3 g (6.8 mmol) of EDC hydrochloride (Tokyo Chemical Industry Co., Ltd.) were added and reacted at room temperature for 2 hours. The solution after the reaction was washed once with 13.0 g of 0.1 mol / L hydrochloric acid, once with 13.0 g of 5% aqueous sodium bicarbonate solution, and once with 13.0 g of ion-exchanged water, and then concentrated using an evaporator. After adding 13 g of hexane to the concentrate, 260 mg of PSQ100B (Fuji Silysia Chemical Ltd.) was added and the mixture was stirred at room temperature for 30 minutes. After filtering off the PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried under vacuum to obtain 3.7 g of tert-butyl 4-(2-hexadecyl octadecanoyloxy)phenylacetate (yield: 86 mol% / tert-butyl 4-hydroxyphenylacetate).

[0138] 4-(2-hexadecyloctadecanoyloxy)phenylacetate-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.87-0.90 (t, 6H), δ1.10-1.90 (m, 69H), δ2.50-2.60 (m, 1H), δ3.51 (s, 2H), δ7.00-7.01 (d, 2H), δ7.26-7.28 (d, 2H)

[0139] Step 3: Synthesis of 4-(2-hexadecyloctadecanoyloxy)phenylacetic acid 3.7 g (5.3 mmol) of tert-butyl 4-(2-hexadecyloctadecanoyloxy)phenylacetate was dissolved in 29.3 g of chloroform, and then a solution of 0.8 g (8.3 mmol) of methanesulfonic acid diluted in 7.3 g of chloroform was added and reacted at room temperature for 3 hours. The solution after the reaction was washed three times with 36.6 g of ion-exchanged water and then concentrated using an evaporator. The concentrated crude product was recrystallized using 18.6 g of hexane, and the crystals were collected to obtain 2.9 g of 4-(2-hexadecyloctadecanoyloxy)phenylacetic acid (yield: 84 mol% / tert-butyl 4-(2-hexadecyloctadecanoyloxy)phenylacetate).

[0140] 4-(2-hexadecyloctadecanoyloxy)phenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.87-0.90 (t, 6H), δ1.10-1.90 (m, 60H), δ2.50-2.60 (m, 1H), δ3.51 (s, 2H), δ7.00-7.01 (d, 2H), δ7.26-7.28 (d, 2H)

[0141] Example 3 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate The title compound was synthesized by the method described in Step 1 of Example 1.

[0142] Step 2: Synthesis of 4-(D-α-tocopherol hemisuccinyloxy)phenylacetate-tert-butyl 1.0 g (4.8 mmol) of 4-hydroxyphenylacetate-tert-butyl was dissolved in 20.0 g of chloroform, and then 2.5 g (4.7 mmol) of D-α-tocopherol succinate (manufactured by Tokyo Chemical Industry Co., Ltd.), 120 mg (1.0 mmol) of DMAP (manufactured by Koei Chemical Co., Ltd.), and 1.2 g (6.2 mmol) of EDC hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added and reacted at room temperature for 2 hours. The solution after the reaction was washed once with 20 g of 0.1 mol / L hydrochloric acid, once with 20 g of 5% aqueous sodium bicarbonate solution, and once with 20 g of ion-exchanged water, and then concentrated using an evaporator. 20 g of hexane was added to the concentrate, and then 200 mg of PSQ100B (Fuji Silysia Chemical Ltd.) was added and stirred at room temperature for 30 minutes. After filtering off the PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried in vacuo to obtain 2.5 g of tert-butyl 4-(D-α-tocopherolhemisuccinyloxy)phenylacetate (yield: 80 mol% / tert-butyl 4-hydroxyphenylacetate).

[0143] 4-(D-α-tocopherol hemisuccinyloxy)phenylacetate-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.80-0.90 (t, 12H), δ1.0-1.9 (m, 35H), δ1.96 (s, 3H) δ2.00 (s, 3H), δ2.08 (s, 3H), δ2.55-2.60 (t, 2H), δ2.81-2.84 (t, 2H), δ2.91-2.94 (t, 2H), δ3.50 (s, 2H), δ7.02-7.30 (d, 2H), δ7.26-7.28 (d, 2H)

[0144] Step 3: Synthesis of 4-(D-α-tocopherol hemisuccinyloxy)phenylacetic acid 1.4 g (2.0 mmol) of tert-butyl 4-(D-α-tocopherol hemisuccinyloxy)phenylacetate was dissolved in 12.0 g of chloroform, and then a solution prepared by diluting 0.3 g (3.2 mmol) of methanesulfonic acid in 2.0 g of chloroform was added and reacted at room temperature for 3 hours. After the reaction, the solution was washed three times with 12.1 g of ion-exchanged water and then concentrated using an evaporator. The concentrated crude product was recrystallized using 4.5 g of hexane, and the crystals were collected to obtain 0.6 g of 4-(D-α-tocopherol hemisuccinyloxy)phenylacetic acid (yield: 55 mol% / tert-butyl 4-(D-α-tocopherol hemisuccinyloxy)phenylacetate).

[0145] 4-(D-α-tocopherol hemisuccinyloxy)phenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.80-0.90 (t, 12H), δ1.0-1.9 (m, 26H), δ1.96 (s, 3H) δ2.00 (s, 3H), δ2.08 (s, 3H), δ2.55-2.60 (t, 2H), δ2.81-2.84 (t, 2H), δ2.91-2.94 (t, 2H), δ3.66 (s, 2H), δ7.02-7.30 (d, 2H), δ7.28-7.32 (d, 2H)

[0146] Example 4 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate The title compound was synthesized by the method described in Step 1 of Example 1.

[0147] Step 2: Synthesis of 4-linoleoyloxyphenylacetate-tert-butyl 1.0 g (4.8 mmol) of 4-hydroxyphenylacetate-tert-butyl was dissolved in 10.0 g of chloroform, followed by the addition of 1.0 g (4.7 mmol) of linoleic acid (NOF Corporation), 120 mg (1.0 mmol) of DMAP (Koei Chemical Co., Ltd.), and 1.2 g (6.2 mmol) of EDC hydrochloride (Tokyo Chemical Industry Co., Ltd.), and the reaction was carried out at room temperature for 2 hours. The reaction solution was washed once with 10 g of 0.1 mol / L hydrochloric acid, once with 10 g of 5% aqueous sodium bicarbonate solution, and once with 10 g of ion-exchanged water, and then concentrated using an evaporator. 10 g of hexane was added to the concentrate, and then 200 mg of PSQ100B (Fuji Silysia Chemical Ltd.) was added and the mixture was stirred at room temperature for 30 minutes. After filtering off PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried in vacuo to obtain 1.8 g of tert-butyl 4-linoleoyloxyphenylacetate (yield: 80 mol % / tert-butyl 4-hydroxyphenylacetate).

[0148] 4-linoleoyloxyphenylacetic acid-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.87-0.90 (t, 3H), δ1.20-1.40 (m, 23H), δ1.55-1.62 (m, 2H), δ1.97-2.07 (m, 4H), δ2.27-2.30 (t, 2H), δ2.76-2.78 (t, 2H), δ3.50 (s, 2H), δ5.32-5.39 (m, 4H), δ7.02-7.30 (d, 2H), δ7.26-7.28 (d, 2H)

[0149] Step 3: Synthesis of 4-linoleoyloxyphenylacetic acid 1.0 g (2.0 mmol) of tert-butyl 4-linoleoyloxyphenylacetate was dissolved in 4.0 g of acetonitrile and 4.0 g of chloroform, and then a solution of 0.3 g (3.2 mmol) of methanesulfonic acid diluted in 1.0 g of acetonitrile and 1.0 g of chloroform was added and reacted at room temperature for 3 hours. The solution after the reaction was washed three times with 10.0 g of ion-exchanged water and then concentrated using an evaporator. The concentrated crude product was recrystallized using 3 g of hexane, and the crystals were collected to obtain 0.5 g of 4-linoleoyloxyphenylacetic acid (yield: 60 mol% / tert-butyl 4-linoleoyloxyphenylacetate).

[0150] 4-linoleoyloxyphenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.87-0.90 (t, 3H), δ1.20-1.40 (m, 14H), δ1.55-1.62 (m, 2H), δ1.97-2.07 (m, 4H), δ2.27-2.30 (t, 2H), δ2.76-2.78 (t, 2H), δ3.66 (s, 2H), δ5.32-5.39 (m, 4H), δ7.02-7.30 (d, 2H), δ7.28-7.32 (d, 2H)

[0151] Example 5 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate The title compound was synthesized by the method described in Step 1 of Example 1.

[0152] Step 2: Synthesis of 4-(2-hexyldecanoyloxy)phenylacetate-tert-butyl 1.0 g (4.8 mmol) of 4-hydroxyphenylacetate-tert-butyl was dissolved in 10.0 g of chloroform, and then 1.2 g (4.7 mmol) of 2-hexyldecanoic acid (Tokyo Chemical Industry Co., Ltd.), 120 mg (1.0 mmol) of DMAP (Koei Chemical Co., Ltd.), and 1.2 g (6.2 mmol) of EDC hydrochloride (Tokyo Chemical Industry Co., Ltd.) were added and reacted at room temperature for 2 hours. The reaction solution after the reaction was washed once with 10 g of 0.1 mol / L hydrochloric acid, once with 10 g of 5% aqueous sodium bicarbonate solution, and once with 10 g of ion-exchanged water, and then concentrated using an evaporator. 10 g of hexane was added to the concentrate, and 200 mg of PSQ100B (Fuji Silysia Chemical Ltd.) was added and stirred at room temperature for 30 minutes. After filtering off PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried in vacuo to obtain 1.7 g of tert-butyl 4-(2-hexyldecanoyloxy)phenylacetate (yield: 80 mol % / tert-butyl 4-hydroxyphenylacetate).

[0153] 4-(2-hexyldecanoyloxy)phenylacetate-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.77-0.89 (t, 6H), δ1.27-1.42 (m, 29H), δ1.71-1.77 (m, 4H), δ2.52-2.56 (m, 1H), δ3.50 (s, 2H), δ7.02-7.30 (d, 2H), δ7.26-7.28 (d, 2H)

[0154] Step 3: Synthesis of 4-(2-hexyldecanoyloxy)phenylacetic acid 1.0 g (2.2 mmol) of tert-butyl 4-(2-hexyldecanoyloxy)phenylacetate was dissolved in 4.0 g of acetonitrile and 4.0 g of chloroform, and then a solution of 0.3 g (3.6 mmol) of methanesulfonic acid diluted in 1.0 g of acetonitrile and 1.0 g of chloroform was added and reacted at room temperature for 3 hours. The solution after the reaction was washed three times with 10.0 g of ion-exchanged water and then concentrated using an evaporator. The concentrated crude product was recrystallized using 3 g of hexane, and the crystals were collected to obtain 0.5 g of 4-(2-hexyldecanoyloxy)phenylacetic acid (yield: 55 mol% / tert-butyl 4-(2-hexyldecanoyloxy)phenylacetate).

[0155] 4-(2-hexyldecanoyloxy)phenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.77-0.89 (t, 6H), δ1.27-1.42 (m, 20H), δ1.71-1.77 (m, 4H), δ2.52-2.56 (m, 1H), δ3.64 (s, 2H), δ7.03-7.06 (m, 2H), δ7.28-7.31 (m, 2H)

[0156] Example 6 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate The title compound was synthesized by the method described in Step 1 of Example 1.

[0157] Step 2: Synthesis of tert-butyl 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetate 1.0 g (4.8 mmol) of tert-butyl 4-hydroxyphenylacetate was dissolved in 10.0 g of chloroform, and then 2.0 g (4.7 mmol) of 9-(heptadecan-9-yloxy)-9-oxononanoic acid (synthesized by the method described in Patent Document 3), 120 mg (1.0 mmol) of DMAP (manufactured by Koei Chemical Co., Ltd.), and 1.2 g (6.2 mmol) of EDC hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd.) were added and reacted at room temperature for 2 hours. The solution after the reaction was washed once with 15 g of 0.1 mol / L hydrochloric acid, once with 15 g of a 5% aqueous solution of sodium bicarbonate, and once with 15 g of ion-exchanged water, and then concentrated using an evaporator. After adding 15 g of hexane to the concentrate, 200 mg of PSQ100B (Fuji Silysia Chemical Ltd.) was added and the mixture was stirred at room temperature for 30 minutes. After filtering off the PSQ100B, the filtrate was concentrated using an evaporator, and the concentrate was dried under vacuum to obtain 2.4 g of tert-butyl 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetate (yield: 80 mol% / tert-butyl 4-hydroxyphenylacetate).

[0158] 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetate-tert-butyl １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.84-0.90 (t, 6H), δ1.20-1.40 (m, 39H), δ1.55-1.70 (m, 4H), δ1.40-1.50 (m, 4H), δ2.25 -2.34 (m, 4H), δ4.80-4.90 (m, 1H), δ3.50 (s, 2H), δ7.02-7.30 (d, 2H), δ7.26-7.28 (d, 2H)

[0159] Step 3: Synthesis of 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetic acid 1.2 g (2.0 mmol) of tert-butyl 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetate was dissolved in 10.0 g of chloroform, and then a solution of 0.3 g (3.2 mmol) of methanesulfonic acid diluted in 2.0 g of chloroform was added and reacted at room temperature for 3 hours. The solution after the reaction was washed three times with 14.0 g of ion-exchanged water and then concentrated using an evaporator. The crude product after concentration was recrystallized using 3.6 g of hexane, and the crystals were collected to obtain 0.6 g of 4-(9-(heptadecan-9-yloxy)-9-oxononanoyl)oxyphenylacetic acid (yield: 55 mol % / tert-butyl 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetate).

[0160] 4-(9-(heptadecan-9-yloxy)-9-oxononanoyloxy)phenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.84-0.90 (t, 6H), δ1.20-1.40 (m, 30H), δ1.55-1.70 (m, 4H), δ1.40-1.50 (m, 4H), δ2.25 -2.34 (m, 4H), δ4.80-4.90 (m, 1H), δ3.66 (s, 2H), δ7.02-7.30 (d, 2H), δ7.28-7.32 (d, 2H)

[0161] Example 7 Step 1: Synthesis of tert-butyl 4-hydroxyphenylacetate 19.20 kg of tert-butyl alcohol and 4800 g of toluene were added to 6077 g (54.2 mol) of potassium tert-butoxide (Kanto Chemical Co., Ltd.) and dissolved. A solution of 4800 g of tert-butyl alcohol and 1200 g of toluene dissolved in 3000 g (18.1 mol) of methyl 4-hydroxyphenylacetate (Tokyo Chemical Industry Co., Ltd.) was added, and the reaction was carried out at 40°C for 2 hours. The reaction solution was neutralized by adding a solution prepared by diluting 6300 g of phosphoric acid in 12.00 kg of methanol, and the precipitated salt was filtered off, and the filtrate was concentrated using an evaporator. 15.75 kg of a 5% aqueous solution of sodium bicarbonate was added to the concentrate, and extraction was carried out twice using 25.50 kg of dichloromethane. The dichloromethane layers obtained by the two extractions were collected and mixed, and then 600 g of magnesium oxide / aluminum oxide adsorbent KW-2000 (Kyowa Chemical Industry Co., Ltd.) was added and stirred at room temperature for 30 minutes. The KW-2000 was filtered off, and the resulting solution was concentrated using an evaporator. 9000 g of toluene was added to the concentrate and the mixture was concentrated again using an evaporator. This procedure was repeated twice, and the resulting crystals were vacuum-dried to obtain 2935 g of tert-butyl 4-hydroxyphenylacetate (yield 78 mol% / methyl 4-hydroxyphenylacetate).

[0162] Step 2: Synthesis of 4-oleoyloxyphenylacetate-tert-butyl 20.0 g (0.096 mol) of 4-hydroxyphenylacetate-tert-butyl was dissolved in 200 g of chloroform, and then 29.9 g (0.106 mol) of oleic acid (NOF Corporation), 2.35 g (0.019 mol) of DMAP, and 23.9 g (0.125 mol) of EDC hydrochloride (Tokyo Chemical Industry Co., Ltd.) were added and reacted at room temperature for 1 hour. The reaction solution was washed once with 200 g of ion-exchanged water, once with 200 g of 0.1 mol / L hydrochloric acid and 100 g of tert-butyl alcohol, once with 200 g of 5% aqueous sodium bicarbonate solution, and once with 100 g of ion-exchanged water, and then concentrated using an evaporator. 200 g of hexane was added to the concentrate, followed by the addition of 4 g of silica gel PSQ100B (Fuji Silysia Chemical Ltd.) and stirring at room temperature for 30 minutes. After filtering off the PSQ100B, 20 g of hydrotalcite adsorbent KW-1000 (Kyowa Chemical Industry Co., Ltd.) was added and stirred at room temperature for 30 minutes. After filtering off the KW-1000, the mixture was concentrated using an evaporator, and the concentrate was dried under vacuum to obtain 42.7 g of 4-oleoyloxyphenylacetate-tert-butyl (yield 94 mol% / 4-hydroxyphenylacetate-tert-butyl).

[0163] Step 3: Synthesis of 4-oleoyloxyphenylacetic acid 25.0 g (0.053 mol) of tert-butyl 4-oleoyloxyphenylacetate was dissolved in 100 g of acetonitrile, and then a solution of 8.13 g (0.085 mol) of methanesulfonic acid diluted in 25 g of acetonitrile was added and reacted at room temperature for 2 hours. 125 g of chloroform was added to the reaction solution, and the mixture was washed three times with 125 g of ion-exchanged water. After washing, 1.29 g (0.011 mol) of DMAP and 25 g of ion-exchanged water were added, and the mixture was stirred for 30 minutes. The mixture was washed once with 125 g of 0.1 mol / L hydrochloric acid and twice with 125 g of ion-exchanged water. After concentration using an evaporator, the mixture was recrystallized using 68 g of hexane, and the crystals were collected to obtain 16.0 g of 4-oleoyloxyphenylacetic acid (yield 73 mol% / tert-butyl 4-oleoyloxyphenylacetate).

[0164] Comparative Example 1 Synthesis of oleic anhydride by the method described in Patent Document 2 7.0 g (24.8 mmol) of oleic acid (NOF Corporation) was dissolved in 56 g of chloroform at room temperature and cooled to 10-15°C. A suspension prepared by dissolving 2.5 g (12.1 mmol) of DCC (Osaka Synthetic Organic Chemical Research Institute, Ltd.) in 14 g of chloroform was added dropwise thereto, and the reaction was carried out at 10-25°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated using an evaporator. The obtained concentrate was redissolved in 21 g of hexane, and insoluble matter was removed by filtration. The obtained filtrate was concentrated using an evaporator, yielding 6.0 g of oleic anhydride.

[0165] Synthesis of 4-oleoyloxyphenylacetic acid: 4.3 g (7.9 mmol) of oleic anhydride and 0.6 g (3.9 mmol) of 4-hydroxyphenylacetic acid (Tokyo Chemical Industry Co., Ltd.) were dissolved in 65 g of chloroform. 0.2 g (1.6 mmol) of DMAP (Koei Chemical Co., Ltd.) was added thereto, and the reaction was carried out at room temperature for 9 hours. The reaction solution was washed twice with 22 g of 10% aqueous acetic acid solution and twice with 22 g of ion-exchanged water, after which 1.3 g of magnesium sulfate (Kanto Chemical Co., Inc.) was added to the organic layer and stirred for 30 minutes. After filtering off the magnesium sulfate, the filtrate was concentrated using an evaporator. The concentrate was redissolved in 28 g of hexane, and after filtering off the insoluble matter, extraction was carried out six times using 17 g of acetonitrile. The acetonitrile layer was collected and concentrated using an evaporator to obtain 1.8 g of the same 4-oleoyloxyphenylacetic acid as in Example 1 (yield: 37 mol % / 4-hydroxyphenylacetic acid) (yield: 24 mol % / oleic acid) (cf. Example 1 yield: 59 mol % / oleic acid).

[0166] 4-oleoyloxyphenylacetic acid １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.89-0.91 (t, 3H), δ1.20-1.57 (m, 20H), δ1.72-1.85 (m, 2H), δ2.00-2.10 (m, 4H), δ2.52 -2.70 (t, 2H), δ3.66 (s, 2H), δ5.30-5.40 (m, 2H), δ7.02-7.30 (d, 2H), δ7.28-7.32 (d, 2H)

[0167] [Analysis Method] 100 μL of the solution after the reaction in Examples 1 to 7 and Comparative Example 1 was taken and mixed with 1 mL of deuterated chloroform. １ H-NMR measurement was carried out. The integral values ​​of all peaks between 3.5 ppm and 4.0 ppm, which correspond to the benzyl position of the 4-hydroxyphenylacetic acid structure (theoretical integral value: 2), were set to 2.000, and the integral value of the methylene peak at 3.84 ppm, which is specific to oligomers of 4-hydroxyphenylacetic acid, was determined to calculate the molar amount of the oligomer relative to the 4-hydroxyphenylacetic acid structure. Note that the integral value was set to detect up to 0.001, so the detection limit was 0.05 mol% (= 0.001 / 2.000). The results are shown in Table 2.

[0168]

[0169] From the above results, no oligomers were detected in the examples, and the amount of oligomers was successfully reduced compared to Comparative Example 1. Therefore, this production method is useful as a method for producing chemical substances used as pharmaceuticals and their raw materials.

[0170] [Example 8] Step 4: Synthesis of O-Ph-P4C2 48.0 g (0.13 mol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide (di-4PE form) synthesized by the method described in US 2014 / 0335157 A1, 111.5 g (0.27 mol) of 4-oleoyloxyphenylacetic acid obtained by the method of Example 1, and 6.2 g (0.05 mol) of DMAP were dissolved in 1680 g of dichloromethane at room temperature. 73.3 g (0.38 mol) of EDC was added thereto, and the mixture was allowed to react at 20-30°C for 21 hours. The reaction solution was washed twice with 1200 g of ion-exchanged water, and then the organic layer was concentrated using an evaporator to obtain 161 g of a crude product. The obtained crude product was purified using a column to obtain 117.5 g of O-Ph-P4C2.

[0171] O-Ph-P4C2 １ H-NMR spectrum (600 MHz, CDCl ３) δ0.86-0.90 (t, 6H), δ1.22-1.42 (m, 46H), δ1.54-1.76 (m, 12H), δ1.94-2.03 (m, 12H), δ2.52-2.56 (m, 4H), δ2.62-2.66 (m , 4H), δ2.80-2.89 (m, 8H), δ3.59 (s, 4H), δ4.11-4.14 (t, 4H), δ5.34-5.37 (m, 4H), δ7.02-7.05 (m, 4H), δ7.26-7.30 (m, 4H)

[0172] [Example 9] Step 4: Synthesis of E-Ph-P4C2 0.350 g (0.929 mmol) of di-4PE, 1.04 g (1.95 mmol) of 4-(D-α-tocopherolhemisuccinyloxy)phenylacetic acid obtained by the method of Example 3, and 0.0454 g (0.372 mmol) of DMAP were dissolved in 10.5 g of chloroform at room temperature. 0.534 g (2.79 mmol) of EDC was added thereto, and the mixture was allowed to react at 30-35°C for 4 hours. The reaction solution was washed twice with 7.00 g of 20% saline and then dehydrated using 0.350 g of magnesium sulfate. After filtering the magnesium sulfate, the filtrate was concentrated using an evaporator to obtain 1.31 g of a crude product. The obtained crude product was purified using a column to obtain 0.860 g of E-Ph-P4C2.

[0173] E-Ph-P4C2 １ H-NMR spectrum (600 MHz, CDCl ３ ) δ0.83-0.87 (m, 24H), δ1.02-1.85 (m, 66H), δ1.94-1.98 (m, 10H), δ2.00 (s, 6H), δ2.08 (s, 6H), δ2.53-2.66 (m, 8H), δ2.71-2.85 (m, 8H), δ2.85-2.95 (m, 8H), δ3.65 (s, 4H), δ4.11-4.14 (t, 4H), δ7.05-7.08 (m, 2H), δ7.27-7.31 (m, 2H)

[0174] The production method of the present invention can be used as a production method for raw materials for pharmaceuticals that require high purity products, LNP raw materials, etc. The cationic lipids produced by the production method of the present invention are useful as LNP raw materials.

[0175] This application is based on patent application No. 2022-051920 filed in Japan, the contents of which are incorporated in their entirety herein.

Claims

1. A method for producing a carboxylic acid containing an aryl ester represented by the following general formula (1), comprising the following three steps: (Step 1) reacting a compound represented by the following general formula (7) with potassium tert-butoxide and tert-butyl alcohol in the presence of an aprotic solvent to obtain a compound represented by the following general formula (11): (Step 2) reacting a compound represented by the following general formula (11) with a compound represented by the following general formula (13) using a condensing agent to obtain a compound represented by the following general formula (12): (Step 3) deprotecting the tert-butyl group of a compound represented by the following general formula (12) using trifluoromethanesulfonic acid, methanesulfonic acid, a combination of trimethylsilyl chloride (TMS-Cl) and sodium iodide, or trimethylsilyl iodide (TMS-I) in an organic solvent to obtain a compound represented by the following general formula (1); 【Chemistry 1】 In general formula (1), A is a group represented by the following general formula (2), (3), or (4), and n is an integer of 1 to 10 representing the number of repeating methylene group units: 【Chemistry 2】 In general formula (2), R １ ~R ５ at least one selected from the following is a group represented by general formula (5), and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group: In general formula (3), R ６ ~R １２ at least one selected from the following is a group represented by general formula (5), and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group: In general formula (4), R １３ ~R １９ at least one selected from the following is a group represented by general formula (5), and the remaining are each independently a hydrogen atom, a halogen atom, or an alkyl group: 【Transformation 3】 In general formula (5), R ２０ is structure I, II, or III shown below, I: a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue; II: A group represented by the following general formula (6): 【Chemistry 4】 In the general formula (6), k is an integer of 2 to 10 representing the number of repeating methylene units, and R ２１ is a linear aliphatic hydrocarbon group having 12 to 22 carbon atoms, a branched aliphatic hydrocarbon group having 12 to 37 carbon atoms, a fat-soluble vitamin residue, or a sterol derivative residue, III: a group containing a benzene ring and a guanidino group and consisting of 7 or 8 carbon atoms, 3 nitrogen atoms, and a hydrogen atom; 【Transformation 5】 In the general formula (7), B is a group represented by the following general formula (8), (9), or (10), n is an integer of 1 to 10 representing the number of repeating methylene groups, and R ２２ is methyl or ethyl, 【Transformation 6】 In general formula (8), R ２３ ~R ２７ at least one selected from the group consisting of: is a hydroxy group, and the remaining groups are each independently a hydrogen atom, a halogen atom, or an alkyl group; In general formula (9), R ２８ ~R ３４ at least one selected from the group consisting of: is a hydroxy group, and the remaining groups are each independently a hydrogen atom, a halogen atom, or an alkyl group; In general formula (10), R ３５ ~R ４１ at least one selected from is a hydroxy group, and the rest are each independently a hydrogen atom, a halogen atom, or an alkyl group; 【Transformation 7】 In the general formula (11), B is a group represented by the general formula (8), (9), or (10), and n is an integer of 1 to 10 representing the number of repeating methylene groups; 【Transformation 8】 In general formula (13), R ２０ is structure I, II, or III shown above; 【Chemistry 9】 In the general formula (12), A is a group represented by the general formula (2), (3), or (4), and n is an integer of 1 to 10 representing the number of repeating methylene groups.

2. 2. The method according to claim 1, wherein A in the general formulas (1) and (12) is a group represented by the general formula (2), and B in the general formulas (7) and (11) is a group represented by the general formula (8).

3. In the general formula (2), R １ ~R ５ At least one selected from the group represented by the general formula (5) is a group represented by the general formula (5), and the remaining groups are each independently a hydrogen atom; and in the general formula (8), R ２３ ~R ２７ 3. The method according to claim 2, wherein at least one selected from the group consisting of: is a hydroxy group; and the remaining groups are each independently a hydrogen atom.

4. In the general formula (2), R ３ is a group represented by the general formula (5), and R １ , R ２ , R ４ , and R ５ are each independently a hydrogen atom, and in the general formula (8), R ２５ is a hydroxy group, and R ２３ , R ２４ , R ２６ , and R ２７ The method according to claim 2, wherein each of the groups independently represents a hydrogen atom.

5. R in the general formulas (5) and (13) ２０ The method according to any one of claims 1 to 4, wherein:

6. The method according to any one of claims 1 to 4, wherein n is 1.

7. The method according to any one of claims 1 to 4, wherein methanesulfonic acid is used in the step 3.

8. The method according to any one of claims 1 to 4, wherein the aprotic solvent in (Step 1) is toluene.

9. The method according to any one of claims 1 to 4, wherein the condensing agent described in (Step 2) is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N,N'-dicyclohexylcarbodiimide (DCC), and N,N'-diisopropylcarbodiimide (DIC).

10. The method according to any one of claims 1 to 4, wherein the organic solvent described in (Step 3) is acetonitrile, dichloromethane, chloroform, or a mixture thereof.

11. In the general formula (7), R ２２ The method according to any one of claims 1 to 4, wherein is methyl.

12. (Step 1), (Step 2) and (Step 3) according to any one of claims 1 to 4; (Step 4) A method for producing a cationic lipid, comprising: condensing the obtained carboxylic acid containing an aryl ester represented by general formula (1) with a compound having a disulfide bond, at least one tertiary nitrogen, and at least one hydroxyl group or amino group.

13. The compound is a compound represented by general formula (14), The method for producing a cationic lipid according to claim 12, wherein in the step 4, the carboxylic acid containing the aryl ester and the hydroxy group of the compound are condensed to obtain a cationic lipid represented by general formula (20): 【Chemistry 10】 In general formula (14), R ４２ and R ４２ａ each independently represents an alkylene group having 1 to 6 carbon atoms, R ４３ and R ４３ａ each independently represents a non-cyclic alkyl tertiary amino group having 1 to 6 carbon atoms and one tertiary amino group, or a cyclic alkylene tertiary amino group having 2 to 5 carbon atoms and one or two tertiary amino groups, R ４４ and R ４４ａ each independently represents an alkylene group or an oxydialkylene group having 8 or less carbon atoms; 【Chemistry 11】 In formula (20), each symbol has the same meaning as defined above.

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