Compound having disulfide bond and method for producing same

Abstract

The present invention provides a method for producing a compound (1), the method comprising the following step 1a:　step 1a for reacting a compound (3) and a compound (4) in a two-phase system containing an organic base, an inorganic base, water, and a water-insoluble organic solvent, thereby obtaining the compound (1). The definitions of the symbols in the formula are as described in the description.

Description

Compounds having disulfide bonds and methods for producing the same

[0001] The present invention relates to a compound having a disulfide bond that is useful as a synthetic intermediate for ionic lipids having a disulfide bond, and to a method for producing the same.

[0002] In recent years, there has been a surge in the development of pharmaceutical formulations using lipid nanoparticles (LNPs) as carriers for the delivery of nucleic acids such as DNA and mRNA. LNPs are generally composed of ionic lipids, phospholipids, cholesterol, and PEG lipids. Due to their properties for use in pharmaceutical applications, these lipids are required to have few or no impurities. Therefore, the synthetic intermediates used in the production of these lipids are also required to have few or no impurities.

[0003] Ionic lipids, in particular, are the most important components that affect the delivery efficiency and toxicity of nucleic acids and genes. Ionic lipids are uncharged at physiological pH (around 7.4), but are designed to become positively charged in low pH environments. Due to this property, after LNPs are taken up into cells by endocytosis, they interact electrostatically with the anionic cell membrane in the acidic environment of endosomes, promoting membrane fusion or membrane disruption, allowing them to escape from endosomes and release encapsulated nucleic acids in the cytoplasm. Therefore, ionic lipids are required to efficiently escape from endosomes in an appropriate pH response and then rapidly dissociate from nucleic acids, and this functionality is directly linked to the delivery efficiency of nucleic acids.

[0004] Previous research has involved structural modifications to improve its functionality. For example, Patent Document 1 reports an ionic lipid (cationic lipid) that can adjust the pKa of a lipid membrane structure affecting endosomal escape efficiency and achieve high membrane fusion ability. Specifically, Patent Document 1 reports an ionic lipid having a structure in which an aromatic ring is introduced near the lipid moiety and bonded to an amine moiety, and these compounds are linked by disulfide bonds. Because this ionic lipid has disulfide bonds, the disulfide bonds in the lipid membrane structure containing this ionic lipid are cleaved in the cytoplasm, allowing the lipid membrane structure encapsulating nucleic acids to release those nucleic acids in the cytoplasm. This lipid membrane structure containing this ionic lipid has high membrane fusion ability in the endosomal environment and high endosomal escape efficiency, making it possible to efficiently deliver nucleic acids into the cytoplasm.

[0005] Regarding the synthesis method of ionic lipids having disulfide bonds as described above, for example, Patent Document 2 describes synthesizing bis[2-(methanesulfonyloxy)ethyl]disulfide by mesyling the hydroxyl group of the starting material bis(2-hydroxyethyl)disulfide using methanesulfonyl chloride, and using this as a synthetic intermediate.

[0006] International Publication No. 2019 / 188867, International Publication No. 2021 / 195529

[0007] However, the method described in Patent Document 2 for producing bis[2-(methanesulfonyloxy)ethyl] disulfide results in the generation of a large amount of impurities as a by-product. In addition, because bis[2-(methanesulfonyloxy)ethyl] disulfide itself is difficult to crystallize, it is difficult to remove impurities from bis[2-(methanesulfonyloxy)ethyl] disulfide using purification methods such as crystallization and crystal washing, which are commonly used for low molecular weight compounds.

[0008] The present invention has been made in view of the above-mentioned points, and the object of the present invention is to provide a method for producing compounds useful as synthetic intermediates for ionic lipids having disulfide bonds in high purity.

[0009] To achieve the above objective, the present inventors conducted extensive research and found that by using substituted or alternatively substituted benzenesulfonyl chloride instead of methanesulfonyl chloride as described in Patent Document 2, the reaction could be carried out in a two-phase system of organic and aqueous phases, and the amount of by-product impurities was significantly reduced. Furthermore, the product obtained by the above reaction (a compound having a disulfide bond) has a benzene ring derived from the substituted or alternatively substituted benzenesulfonyl chloride, which promotes molecular orientation. As a result, the product becomes easier to crystallize, and it was found that impurities could be easily removed by purification methods such as crystallization and crystal washing. Based on this finding, the present invention is as follows.

[0010] [1] A method for producing the compound represented by formula (1) below, comprising the following step 1a: Step 1a, in which a compound represented by formula (3) below and a compound represented by formula (4) below are reacted in a two-phase system containing an organic base, an inorganic base, water, and a water-insoluble organic solvent to obtain the compound represented by formula (1) below.

[0011]

[0012] (In formula (1), R １ａ and R １ｂ Each of these independently represents an alkylene group having 1 to 6 carbon atoms, and both A's are in formula (2)

[0013]

[0014] (In equation (2), * represents the bond position, and R ２ ~R ６ Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano group, a nitro group, a trifluoromethyl group, or a trifluoromethoxy group.

[0015]

[0016] (In formula (3), R １ａ and R １ｂ As stated above.)

[0017]

[0018] (In formula (4), R ２ ~R ６ are as described above.).

[0019] [2] The production method according to [1] above, wherein the organic base is at least one selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dimethylbenzylamine, N-butyldimethylamine, pyridine, and 4-dimethylaminopyridine.

[0020] [3] The production method according to [1] or [2] above, wherein the inorganic base is at least one selected from the group consisting of sodium carbonate and potassium carbonate.

[0021] [4] The production method according to any one of [1] to [3] above, wherein the water-insoluble organic solvent is at least one selected from the group consisting of chloroform and dichloromethane.

[0022] [5] The production method according to any one of [1] to [4] above, wherein R １ａ and R １ｂ are each independently an alkylene group having 1 to 3 carbon atoms. [6] The production method according to any one of [1] to [4] above, wherein R ２ ~R ６ are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[0023] [7] A compound represented by the following formula (1):

[0024]

[0025] (In formula (1), R １ａ and R １ｂ each independently represent an alkylene group having 1 to 6 carbon atoms, and two A's together are both represented by formula (2):

[0026]

[0027] (In formula (2), * represents the bonding position, and R ２ ~R ６Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano group, a nitro group, a trifluoromethyl group, or a trifluoromethoxy group.

[0028] [8] R １ａ and R １ｂ However, each is independently an alkylene group having 1 to 3 carbon atoms, as described in [7] above. [9] R ２ ~R ６ However, each of these compounds is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, as described in [7] or [8] above.

[0029]

[10] A method for producing a compound represented by the following formula (5), comprising the following steps 2a and 2b: Step 2a, which involves obtaining a compound represented by formula (1) by the production method described in any one of [1] to [6] above; and Step 2b, which involves reacting the compound represented by formula (1), the compound represented by the following formula (6a), and the compound represented by the following formula (6b) to obtain a compound represented by the following formula (5).

[0030]

[0031] (In formula (5), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, and R ７ａ and R ７ｂ Each of these independently represents either an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms.

[0032]

[0033] (In equations (6a) and (6b), X ａ , X ｂ , R ７ａ , and R ７ｂ As stated above, the hydrogen atom at the far right of equation (6a) is X ａIt is bonded to the nitrogen atom inside, and the hydrogen atom at the far right of formula (6b) is X ｂ It is bonded to the nitrogen atom inside.

[0034]

[11] A method for producing an ionic lipid represented by the following formula (7a), comprising the following steps 3a and 3b: Step 3a, which involves obtaining a compound represented by formula (5) by the production method described in

[10] above; and Step 3b, which involves reacting the compound represented by formula (5), the compound represented by the following formula (19a), and the compound represented by the following formula (19b) to obtain an ionic lipid represented by the following formula (7a).

[0035]

[0036] (In formula (7a), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each independently represents an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms, and each independently represents 0 or 1, Z ａ and Z ｂ Each independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, having at least one aromatic ring, and possibly having a heteroatom, and R ８ａ and R ８ｂEach of these independently comprises: (i) a monovalent group having 10 to 50 carbon atoms having one carbonyl group and at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (ii) a monovalent group having 10 to 50 carbon atoms having at least two carbonyl groups (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (iii) formula (8): *-R ９ -X １ -R １０ (8) (In equation (8), * indicates the bonding position, R ９ X represents an alkylene group with 1 to 10 carbon atoms. １ R represents a carbamate bond, carbonate bond, or amide bond, and １０ represents an alkyl group having 1 to 25 carbon atoms, and R １０ (iv) Formula (9): *-R １１ -CO-O-R １２ (9) In equation (9), * represents the bonding position, R １１ R represents an alkylene group having 1 to 10 carbon atoms, and １２ represents an alkyl group having 1 to 25 carbon atoms that is substituted with at least one halogen atom. ) A monovalent group represented by formula (v) (10):

[0037]

[0038] (In equation (10), * represents the bond position, R １３ and R １４ Each of these independently represents an alkylene group with 1 to 10 carbon atoms, an alkenediyl group with 2 to 10 carbon atoms, or an alkynediyl group with 2 to 10 carbon atoms, R １５ ~R １７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution１９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (vi) Formula (11):

[0039]

[0040] (In equation (11), * represents the bonding position, X ２ is a nitrogen atom or formula (12):

[0041]

[0042] (In equation (12), * represents R ２１ This represents the bond position with, and ** is R ２２ or R ２３ This represents the bonding position with ( ). ) represents the trivalent group indicated by X ２ When R is a nitrogen atom, ２１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When is a trivalent group represented by formula (12), R ２１ R represents an alkylene group having 1 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When R is a nitrogen atom, ２２ and R ２３ Each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups, and X ２ When is a trivalent group represented by formula (12), R ２２ and R ２３each independently represents an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ may each independently be substituted with a substituent selected from the group consisting of a halogen atom and a hydroxy group. ) represents a monovalent group represented by, (vii) formula (13):

[0043]

[0044] (In formula (13), * represents a bonding position, and R ２４ is a hydrogen atom, a benzyl group, *-Si(R １８ )(R １９ )(R ２０ group (in the above formula, * represents a bonding position, and R １８ to R ２０ each independently represents an alkyl group having 1 to 4 carbon atoms or a phenyl group. ), or *-CO-R ２５ group (in the above formula, * represents a bonding position, and R ２５ represents an alkyl group having 1 to 9 carbon atoms. ). ) represents a monovalent group represented by, (viii) formula (14):

[0045]

[0046] (In formula (14), * represents a bonding position, and R ２６ and R ２７ each independently represents a hydrogen atom, a benzyl group, or *-Si(R １８ )(R １９ )(R ２０ group (in the above formula, * represents a bonding position, and R １８ to R ２０ each independently represents an alkyl group having 1 to 4 carbon atoms or a phenyl group. ). ) represents a monovalent group represented by, (ix) formula (15):

[0047]

[0048] (In formula (15), * represents a bonding position, and R ２８ is a hydrogen atom, a benzyl group, or *-Si(R １８ )(R １９ )(R ２０) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (x) Formula (16):

[0049]

[0050] (In formula (16), * represents the bonding position, R ２９ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３０ ) represents an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or an alkynyl group having 2 to 30 carbon atoms. ) A monovalent group represented by formula (xi) (17):

[0051]

[0052] (In formula (17), * represents the bond position, and R ３１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３２ and R ３３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms. ) A monovalent group represented by formula (xii) (18):

[0053]

[0054] (In formula (18), * represents the bond position, R ３４ R represents an alkylene group having 1 to 10 carbon atoms, and ３５ and R ３６Each of these independently represents an alkyl group having 1 to 10 carbon atoms.) A monovalent group represented by (xiii) an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or (xiv)R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p represents an integer from 1 to 8.

[0055]

[0056] (In equations (19a) and (19b), X ２ａ and X ２ｂ Each of these independently represents a hydroxyl group or a halogen atom, as well as na, nb, and Z. ａ Z ｂ , R ８ａ , and R ８ｂ This is as stated above.

[0057]

[12] A method for producing the compound represented by formula (20), comprising the following steps 4a to 4c: Step 4a: obtaining the compound represented by formula (5) by the production method described in

[10] above; Step 4b: reacting the compound represented by formula (5), the compound represented by formula (21a), and the compound represented by formula (21b) below to obtain the compound represented by formula (22); and Step 4c: deprotecting the compound represented by formula (22) below to obtain the compound represented by formula (20).

[0058]

[0059] (In formula (20), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂEach of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each of these independently represents an alkylene group having 1 to 8 carbon atoms or an oxydialkylene group having 2 to 8 carbon atoms, and Z ａ and Z ｂ Each of these independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, possessing at least one aromatic ring, and possibly containing a heteroatom.

[0060]

[0061] (In equations (21a) and (21b), X ３ａ and X ３ｂ Each of these independently represents a hydroxyl group or a halogen atom, Z ａ and Z ｂ As stated above, and also Pr １ and Pr ２ Each of these independently represents a protecting group for a hydroxyl group.

[0062]

[0063] (In formula (22), R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ Z ａ Z ｂ , Pr １ , and Pr ２ This is as stated above.

[0064]

[13] A method for producing an ionic lipid represented by the following formula (7b), comprising the following steps 5a and 5b: step 5a, which involves obtaining a compound represented by formula (20) by the production method described in

[12] above; and step 5b, which involves reacting the compound represented by formula (20), the compound represented by the following formula (23a), and the compound represented by the following formula (23b) to obtain an ionic lipid represented by the following formula (7b).

[0065]

[0066] (In formula (7b), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each of these independently represents an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms, Z ａ and Z ｂ Each independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, having at least one aromatic ring, and possibly having a heteroatom, and R ８ａ and R ８ｂ Each of these independently comprises: (i) a monovalent group having 10 to 50 carbon atoms having one carbonyl group and at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (ii) a monovalent group having 10 to 50 carbon atoms having at least two carbonyl groups (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (iii) formula (8): *-R ９ -X １ -R １０ (8) (In equation (8), * indicates the bonding position, R ９ X represents an alkylene group with 1 to 10 carbon atoms. １ R represents a carbamate bond, carbonate bond, or amide bond, and １０ represents an alkyl group having 1 to 25 carbon atoms, and R １０ (iv) Formula (9): *-R １１ -CO-O-R １２(9) In equation (9), * represents the bonding position, R １１ R represents an alkylene group having 1 to 10 carbon atoms, and １２ represents an alkyl group having 1 to 25 carbon atoms that is substituted with at least one halogen atom. ) A monovalent group represented by formula (v) (10):

[0067]

[0068] (In equation (10), * represents the bond position, R １３ and R １４ Each of these independently represents an alkylene group with 1 to 10 carbon atoms, an alkenediyl group with 2 to 10 carbon atoms, or an alkynediyl group with 2 to 10 carbon atoms, R １５ ~R １７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (vi) Formula (11):

[0069]

[0070] (In equation (11), * represents the bonding position, X ２ is a nitrogen atom or formula (12):

[0071]

[0072] (In equation (12), * represents R ２１ This represents the bond position with, and ** is R ２２ or R ２３ This represents the bonding position with ( ). ) represents the trivalent group indicated by X ２ When R is a nitrogen atom, ２１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ２１X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When is a trivalent group represented by formula (12), R ２１ R represents an alkylene group having 1 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When R is a nitrogen atom, ２２ and R ２３ Each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups, and X ２ When is a trivalent group represented by formula (12), R ２２ and R ２３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups. ) A monovalent group represented by formula (vii) (13):

[0073]

[0074] (In formula (13), * represents the bond position, and R ２４ It consists of a hydrogen atom, a benzyl group, and *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) represents a monovalent group represented by ), (viiii) formula (14):

[0075]

[0076] (In formula (14), * represents the bond position, and R ２６ and R ２７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (ix) formula (15):

[0077]

[0078] (In formula (15), * represents the bond position, and R ２８ is a hydrogen atom, a benzyl group, or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (x) Formula (16):

[0079]

[0080] (In equation (16), * indicates the bonding position. R ２９ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３０ ) represents an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or an alkynyl group having 2 to 30 carbon atoms. ) A monovalent group represented by formula (xi) (17):

[0081]

[0082] (In formula (17), * represents the bond position, and R ３１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and３２ and R ３３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms. ) A monovalent group represented by formula (xii) (18):

[0083]

[0084] (In formula (18), * represents the bond position, R ３４ R represents an alkylene group having 1 to 10 carbon atoms, and ３５ and R ３６ Each of these independently represents an alkyl group having 1 to 10 carbon atoms.) A monovalent group represented by (xiii) an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or (xiv)R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p represents an integer from 1 to 8.

[0085]

[0086] (In equations (23a) and (23b), X ４ａ and X ４ｂ Each of these independently represents a hydroxyl group or a halogen atom, and R ８ａ and R ８ｂ This is as stated above.

[0087] According to the manufacturing method of the present invention, compounds having disulfide bonds, which are useful as synthetic intermediates for ionic lipids having disulfide bonds, can be obtained in high purity.

[0088] Embodiments of the present invention will be described below, but the present invention is not limited thereto. The descriptions herein can be combined with each other unless it is clearly stated that they cannot be combined.

[0089] <Groups> First, the groups described herein will be explained in order. In this specification, alkylene groups may be linear or branched. Examples of alkylene groups include methylene groups, ethylene groups, trimethylene groups (-(CH) ２ ) ３ -), propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), tetramethylene group (-(CH ２ ) ４ -), butylene group (-CH(C ２ H ５ )CH ２ -ien-CH ２ CH(C ２ H ５ )-), pentamethylene group (-(CH ２ ) ５ -), hexamethylene group (-(CH ２ ) ６ -), heptamethylene group (-(CH ２ ) ７ -), octamethylene group (-(CH ２ ) ８ -), nonamethylene group (-(CH ２ ) ９ -), decamethylene group (-(CH ２ ) ９ (-) is one example (the "-" in the above formula represents a single bond).

[0090] In this specification, "alkendiyl group" means a divalent group having a structure obtained by removing two hydrogen atoms from an alkene. In this specification, the alkenediyl group may be linear or branched. In this specification, the number of olefinic carbon-carbon double bonds in the alkene or alkenediyl group may be only one or two or more. Examples of alkenediyl groups include ethendiyl group, propendiyl group, butendiyl group, pentendiyl group, hexendiyl group, heptendiyl group, octendiyl group, nonendiyl group, and decendiyl group. In this specification, "compound name + diyl group (e.g., ethendiyl group)" means a divalent group having a structure obtained by removing two hydrogen atoms from the compound.

[0091] In this specification, "alkynediyl group" means a divalent group having a structure obtained by removing two hydrogen atoms from an alkyne. In this specification, the alkynediyl group may be linear or branched. In this specification, the number of carbon-carbon triple bonds in the alkyne or alkynediyl group may be only one or two or more. Examples of alkynediyl groups include ethindiyl group, propindiyl group, butindiyl group, pentindiyl group, hexindiyl group, heptindiyl group, octindiyl group, nonindiyl group, and decinediyl group.

[0092] In this specification, "oxydialkylene group" means a divalent group having a structure in which two alkylene groups are bonded via an oxy group (-O-) (the "-" in the above formula represents a single bond). The description of the alkylene group in "oxydialkylene group" is as described above.

[0093] In this specification, "ester bond" means -CO-O- or -O-CO- (the "-" in the formula represents a single bond). In this specification, "amide bond" means -CO-NH- or -NH-CO- (the "-" in the formula represents a single bond).

[0094] In this specification, "carbamate bond" means -O-CO-NH- or -NH-CO-O- (where "-" represents a single bond). In this specification, "ether bond" means -O- (where "-" represents a single bond).

[0095] In this specification, "carbonate bond" means -O-CO-O- (where "-" in the above formula represents a single bond).

[0096] In this specification, "residue of a fat-soluble vitamin having a hydroxyl group" means a monovalent group having a structure obtained by removing a hydrogen atom from the hydroxyl group of the fat-soluble vitamin. Examples of fat-soluble vitamins having a hydroxyl group include retinol, ergosterol, 7-dehydrocholesterol, calciferol, corcalciferol, dihydroergocalciferol, dihydrotachisterol, tocopherol, and tocotrienol.

[0097] In this specification, "residue of a sterol derivative having a hydroxyl group" refers to a monovalent group having a structure obtained by removing a hydrogen atom from the hydroxyl group of the sterol derivative. Examples of sterol derivatives having a hydroxyl group include cholesterol, cholestanol, stigmasterol, β-sitosterol, lanosterol, and ergosterol.

[0098] In this specification, alkyl groups may be linear or branched. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl groups. Examples include henicosyl group, docosyl group, tricosyl group, tetracosyl group, pentacosyl group, hexacosyl group, heptacosyl group, octacosyl group, nonacosyl group, triacontyl group, hentriacontyl group, dotriacontyl group, tritriacontyl group, tetratriacontyl group, pentatriacontyl group, hexatriacontyl group, tetracontyl group, hentetracontyl group, dotetracontyl group, tritetracontyl group, and tetratetracontyl group.

[0099] In this specification, the alkenyl group may be linear or branched. Also, in this specification, the number of olefinic carbon-carbon double bonds in the alkenyl group may be only one or two or more. Examples of alkenyl groups include etenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, icocenyl, henicocenyl, dococenyl, tricocenyl, tetracocenyl, pentacocenyl, hexacocenyl, heptacocenyl, octacocenyl, nonacocenyl, triacontenyl, hentriacontenyl, and dotriacontenyl groups.

[0100] In this specification, the alkynyl group may be linear or branched. Also, in this specification, the number of carbon-carbon triple bonds in the alkynyl group may be one or two or more. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desinyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadesinyl, heptadecynyl, octadecynyl, nonadesinyl, icosinyl, henicosinyl, docosinyl, tricosinyl, tetracosinyl, pentacosinyl, hexacosinyl, heptacosinyl, octacosinyl, nonacosinyl, triacontinyl, hentriacontinyl, and dotriacontinyl.

[0101] Examples of halogen atoms used herein include fluorine, chlorine, bromine, and iodine atoms.

[0102] In this specification, "carbon ring group having 3 to 12 carbon atoms" means a cyclic group in which the ring is composed of 3 to 12 carbon atoms. Examples of carbon ring groups having 3 to 12 carbon atoms include cycloalkyl groups having 3 to 8 carbon atoms, phenyl groups, naphthyl groups, and adamantyl groups. Examples of cycloalkyl groups having 3 to 8 carbon atoms include cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, cycloheptyl groups, and cyclooctyl groups. The carbon ring group having 3 to 12 carbon atoms is preferably a non-aromatic hydrocarbon ring group having 3 to 12 carbon atoms, more preferably a cycloalkyl group or adamantyl group having 3 to 8 carbon atoms, and even more preferably a cyclohexyl group or adamantyl group.

[0103] In this specification, "3- to 14-membered heterocyclic group" means a heterocyclic group having 3 to 14 ring-forming atoms. Other expressions similar to "3- to 14-membered" have the same meaning. Examples of 3- to 14-membered heterocyclic groups include 5- to 14-membered aromatic heterocyclic groups and 3- to 14-membered non-aromatic heterocyclic groups.

[0104] Examples of 5- to 14-membered aromatic heterocyclic groups as used herein include: (i) 5- to 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl groups; (ii) Benzothiophenyl group, benzofuranyl group, benzimidazolyl group, benzoxazolyl group, benzoisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzotriazolyl group, imidazopyridinyl group, thienopyridinyl group, phlopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, oxazolopyridinyl group, thiazolopyridinyl group, imidazopyridinyl group, imidazopyridinyl group, thienopyridinyl group, phlopyridinyl group, pyrrolopyridinyl group, pyrazolopyridinyl group, ox 8- to 14-membered condensed polycyclic aromatic heterocyclic groups such as zolopyrimidinyl group, thiazolopyrimidinyl group, pyrazolotriazinyl group, naphtho[2,3-b]thienyl group, phenoxathiinyl group, indolyl group, isoindolyl group, 1H-indazolyl group, prinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthylidinyl group, quinoxalinyl group, quinazolinyl group, synnolinyl group, carbazolyl group, β-carbolinyl group, phenantridinyl group, acridinyl group, phenazinyl group, phenothiazinyl group, and phenoxazinyl group.

[0105] In this specification, examples of 3- to 14-membered non-aromatic heterocyclic groups include: (i) azilidinyl group, oxyranyl group, thyranyl group, azetidinyl group, oxetanyl group, thietanyl group, tetrahydrothienyl group, tetrahydrofuranyl group, pyrrolinyl group, pyrrolidinyl group, imidazolinyl group, imidazolidinyl group, oxazolinyl group, oxazolidinyl group, pyrazolidinyl group, pyrazolidinyl group, thiazolinyl group, thiazolidinyl group, tetrahydroisothiazolyl group, tetrahydrooxazolyl group, tetrahydroisooxazolyl group, piperidinyl group, pipe 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as radinyl group, tetrahydropyridinyl group, dihydropyridinyl group, dihydrothiopyranyl group, tetrahydropyrimidinyl group, tetrahydropyridazinyl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, morpholinyl group, thiomorpholinyl group, azepanyl group, diazepanyl group, azepinyl group, oxepanyl group, azokanyl group, diazokanyl group, and dithiolanyl group (e.g., 1,2-dithiolan-3-yl group); (ii) Dihydrobenzofuranyl group, dihydrobenzimidazolyl group, dihydrobenzoxazolyl group, dihydrobenzothiazolyl group, dihydrobenzoisothiazolyl group, dihydronaphtho[2,3-b]thienyl group, tetrahydroisoquinolyl group, tetrahydroquinolyl group, 4H-quinolidinyl group, indolinyl group, isoindolinyl group, tetrahydrothieno[2,3-c]pyridinyl group, tetrahydrobenzoazepinyl group, tetrahydroquinoxalinyl group, tetrahydro 9- to 14-membered condensed polycyclic non-aromatic heterocyclic groups such as lophenanthidinyl group, hexahydrophenothiazinyl group, hexahydrophenoxazinyl group, tetrahydrophthalazinyl group, tetrahydronaphthilidinyl group, tetrahydroquinazolinyl group, tetrahydrosinnolinyl group, tetrahydrocarbazolyl group, tetrahydro-β-carbolinyl group, tetrahydroacridinyl group, tetrahydrophenazinyl group, tetrahydrothioxanthenyl group, and octahydroisoquinolyl group.

[0106] <Method for producing compound (1)> The present invention provides a method for producing the compound represented by the following formula (1). The definitions of the symbols in formula (1) will be described later.

[0107]

[0108] In this specification, the compound represented by formula (1) may be abbreviated as "compound (1)". Compounds represented by other formulas may also be abbreviated in the same way as "compound represented by formula (1)".

[0109] A method for producing compound (1) of the present invention comprises the following step 1a: step 1a, in which a compound represented by formula (3) and a compound represented by formula (4) are reacted in a two-phase system containing an organic base, an inorganic base, water, and a water-insoluble organic solvent to obtain compound (1). The definitions of the symbols in formulas (3) and (4) will be described later.

[0110]

[0111]

[0112] The above-mentioned "two-phase system" refers to a system consisting of an "aqueous phase" in which compound (3) and an inorganic base are dissolved in water, and an "organic phase" in which compound (4) and an organic base are dissolved in a water-insoluble organic solvent, which is immiscible with the aqueous phase.

[0113] In equations (1) and (3), R １ａ and R １ｂ Each of these independently represents an alkylene group having 1 to 6 carbon atoms (preferably 1 to 4, more preferably 1 to 3, and even more preferably 2). １ａ and R １ｂ Preferably, each is independently a methylene group, an ethylene group, a trimethylene group, and a propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), or a tetramethylene group, more preferably both being ethylene groups. １ａ is R １ｂ It may be the same as or different from, but preferably R １ａ is R １ｂ It is the same base as [another base].

[0114] In equation (1), both A's represent the base shown in equation (2) below. The definitions of the symbols in equation (2) will be explained later.

[0115]

[0116] In equation (2), * indicates the bonding position. In equations (2) and (4), R ２ ~R ６ Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano group, a nitro group, a trifluoromethyl group, or a trifluoromethoxy group.

[0117] In this specification, "*" indicates a bond position, not a carbon atom, as described above. Therefore, both "-*" and "-**" described later represent a single bond.

[0118] R ２ ~R ６ Preferably, each is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. More preferably, R ２ is an alkyl group having 1 to 4 carbon atoms, and R ３ ~R ６ Both are hydrogen atoms, or R ２ , R ５ , and R ６ Each of these is independently an alkyl group having 1 to 4 carbon atoms, and R ３ and R ４ Both are hydrogen atoms. More preferably, R ２ is an alkyl group having 1 to 4 carbon atoms, and R ３ ~R ６ Both are hydrogen atoms.

[0119] Below, R １ａ , R １ｂ , and R ２ ~R ６ Preferred combinations are described. In preferred combinations, R １ａ and R １ｂ Each of these is an alkylene group having 1 to 4 carbon atoms, and R ２ ~R ６Each of these is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[0120] In a more preferred combination, R １ａ and R １ｂ These are, independently, a methylene group, an ethylene group, a trimethylene group, and a propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), or a tetramethylene group, and R ２ is an alkyl group having 1 to 4 carbon atoms, and R ３ ~R ６ Both are hydrogen atoms, or R ２ , R ５ , and R ６ Each of these is independently an alkyl group having 1 to 4 carbon atoms, and R ３ and R ４ Both are hydrogen atoms.

[0121] In a more preferable combination, R １ａ and R １ｂ Both are ethylene groups, and R ２ is an alkyl group having 1 to 4 carbon atoms, and R ３ ~R ６ Both are hydrogen atoms, or R ２ , R ５ , and R ６ Each of these is independently an alkyl group having 1 to 4 carbon atoms, and R ３ and R ４ Both are hydrogen atoms.

[0122] In particularly preferred combinations, R １ａ and R １ｂ Both are ethylene groups, and R ２ is an alkyl group having 1 to 4 carbon atoms, and R ３ ~R ６ Both are hydrogen atoms.

[0123] From the viewpoint of yielding the target product (compound (1)), the ratio of compound (4) used is preferably 3 to 10 mol, and more preferably 4 to 6 mol, per 1 mol of compound (3).

[0124] The organic base may be used alone or in combination of two or more types. The organic base is preferably a tertiary amine. More preferably, the organic base is at least one selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dimethylbenzylamine, N-butyldimethylamine, pyridine, and 4-dimethylaminopyridine, even more preferably at least one selected from the group consisting of triethylamine, tributylamine, and diisopropylethylamine, and particularly preferably triethylamine.

[0125] From the viewpoint of promoting the reaction, the ratio of the organic base used is preferably 0.3 to 6 mol, and more preferably 0.5 to 4 mol, per 1 mol of compound (3).

[0126] The inorganic base may be used alone or in combination of two or more types. The inorganic base is preferably an alkali metal salt. Examples of alkali metal salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The inorganic base is more preferably at least one selected from the group consisting of sodium carbonate and potassium carbonate, and even more preferably potassium carbonate.

[0127] From the viewpoint of promoting the reaction, the ratio of inorganic base used is preferably 3 to 10 mol, and more preferably 5 to 8 mol, per 1 mol of compound (3).

[0128] From the viewpoint of promoting the reaction, the amount of water used is preferably 10 to 50 g, and more preferably 20 to 30 g, per 1 g of compound (3).

[0129] The non-water-soluble organic solvent is not particularly limited as long as it is inert to compounds (3) and (4) and is immiscible with water. Examples of non-water-soluble organic solvents include chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, hexane, and heptane. The non-water-soluble organic solvent is preferably at least one selected from the group consisting of chloroform and dichloromethane, and more preferably chloroform.

[0130] From the viewpoint of dissolving the reactants and promoting the reaction, the ratio of the non-water-soluble organic solvent used is preferably 10 to 50 g, and more preferably 20 to 30 g, per 1 g of compound (3).

[0131] Compound (3) is preferably added to the reaction system in the form of an aqueous solution. The organic base is preferably added to the reaction system in the form of a solution dissolved in a water-insoluble organic solvent. The inorganic base is preferably added to the reaction system in the form of an aqueous solution. It is preferable to mix the aqueous solution of compound (3), the organic base solution (solvent: water-insoluble organic solvent), and the aqueous solution of the inorganic base, and then add compound (4) to the mixture to carry out the reaction.

[0132] The reaction temperature in step 1a is preferably 10 to 40°C, and more preferably 20 to 30°C, from the viewpoint of promoting the reaction. The reaction time in step 1a is not particularly limited, but is preferably 1 to 96 hours, and more preferably 2 to 48 hours.

[0133] After the reaction in step 1a, it is preferable to recover the organic phase from the two-phase system and wash it with an aqueous solution of an inorganic base. Washing with an aqueous solution of an inorganic base may be performed only once or multiple times. This washing can quench compound (4) in the organic phase. Only one type of inorganic base may be used for washing, or two or more types may be used in combination. The inorganic base for washing is preferably an alkali metal salt. Examples of alkali metal salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. More preferably, the inorganic base for washing is at least one selected from the group consisting of sodium carbonate and potassium carbonate, and even more preferably potassium carbonate.

[0134] The concentration of the inorganic base in the aqueous solution used for washing is preferably 0.1 to 30% by weight, more preferably 1 to 10% by weight, from the viewpoint of good quenching of compound (4).

[0135] The temperature at which washing is performed with an aqueous solution of an inorganic base is preferably 10 to 40°C, and more preferably 20 to 30°C.

[0136] It is preferable to wash the organic phase with an acidic aqueous solution after washing with an aqueous solution of an inorganic base. Washing with the acidic aqueous solution may be performed only once or multiple times. This washing can remove organic bases and other substances from the organic phase. Examples of acids for washing include acetic acid, oxalic acid, citric acid, phosphoric acid, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. Preferably, the acid is at least one selected from the group consisting of sodium dihydrogen phosphate and potassium dihydrogen phosphate, and more preferably sodium dihydrogen phosphate.

[0137] The concentration of the acid in the aqueous solution used for cleaning is preferably 0.1 to 30% by weight, more preferably 1 to 10% by weight. The temperature when cleaning with the aqueous acid solution is preferably 10 to 40°C, more preferably 20 to 30°C.

[0138] After washing with an aqueous acid solution, it is preferable to wash the organic phase with saline solution. Washing with saline solution may be performed only once or multiple times. The concentration of the saline solution used for washing is preferably 5 to 25% by weight, more preferably 10 to 20% by weight. The temperature when washing with saline solution is preferably 10 to 40°C, more preferably 20 to 30°C.

[0139] After washing with saline solution, the organic phase is concentrated using an evaporator or the like, and the concentrate is mixed with a solvent to precipitate the target product (compound (1)), thereby obtaining the purified target product. Examples of solvents for this precipitation include water, acetonitrile, acetone, methanol, ethanol, 2-propanol, chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, hexane, heptane, and toluene. Only one solvent may be used, or two or more may be used in combination. The solvent for precipitation is preferably ethanol. The temperature during precipitation is preferably 0 to 80°C, and more preferably 10 to 60°C.

[0140] According to the present invention, it is possible to obtain compound (1) with a purity of 98% by weight or more as measured by thin-layer chromatography (TLC).

[0141] <Compound (1)> The present invention also provides compound (1). Compound (1) of the present invention is useful as a synthesis intermediate for ionic lipids. Ionic lipids can be produced by using compound (1) of the present invention by the production method described below. The description of the groups in compound (1) is the same as the description in <Production Method of Compound (1)> above.

[0142] <Method for producing compound (5)> The present invention provides a method for producing the compound represented by the following formula (5). The definitions of the symbols in formula (5) will be described later.

[0143]

[0144] The method for producing compound (5) of the present invention comprises the following steps 2a and 2b: step 2a, which involves obtaining compound (1) by the method for producing compound (1) of the present invention; and step 2b, which involves reacting compound (1) with the compound represented by the following formula (6a) and the compound represented by the following formula (6b) to obtain compound (5). The definitions of the symbols in formulas (6a) and (6b) will be described later.

[0145]

[0146] R in equation (5) １ａ and R １ｂ The explanation is the same as the explanation in the above section <Method for producing compound (1)>.

[0147] In equations (5), (6a), and (6b), X ａ and X ｂ Each of these independently represents an acyclic or cyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 (preferably 1 to 6) carbon atoms. The amino group is preferably an acyclic alkyl tertiary amino group having 1 to 6 carbon atoms, or an alkylene tertiary amino group having 1 or 2 nitrogen atoms and 2 or 5 carbon atoms.

[0148] In this specification, “acyclic alkyl tertiary amino group having 1 to 6 carbon atoms” means formula (24):

[0149]

[0150] (In formula (24), * represents the bond position, and R ３７ ) represents an alkyl group having 1 to 6 carbon atoms. ) refers to a divalent group represented by ).

[0151] R in equation (24) ３７ The group is preferably a methyl group, an ethyl group, a propyl group, or an isopropyl group, and more preferably a methyl group.

[0152] In this specification, "cyclic alkylene tertiary amino group having 1 or 2 nitrogen atoms and 2 to 5 carbon atoms" means a divalent group in which an alkylene group having 2 to 5 carbon atoms and a tertiary amino group form a cyclic structure, and the cyclic structure contains 1 or 2 tertiary amino groups. The number of carbon atoms is preferably 4 or 5.

[0153] Examples of alkylene tertiary amino groups having one or two nitrogen atoms and two to five carbon atoms include aziridinediyl group, azetidinediyl group, pyrrolidinediyl group, piperidinediyl group, imidazolidinediyl group, and piperazinediyl group.

[0154] A cyclic alkylene tertiary amino group having 1 nitrogen atom and 2 to 5 carbon atoms is preferably of formula (25):

[0155]

[0156] (In formula (25), * is R in formula (5), formula (6a), formula (6b), formula (7a), formula (20), formula (22), or formula (7b) below. １ａ or R １ｂ This indicates the bonding position with, where ** represents R in formula (5), formula (6a), formula (6b), formula (7a), formula (20), formula (22), or formula (7b). ７ａ or R ７ｂ It is a divalent group represented by , where q represents 1 or 2, and q represents the bonding position with .

[0157] Hereinafter, the "divalent group represented by formula (25)" may be abbreviated as "group (25)". Groups represented by other formulas may also be abbreviated in the same way as the "divalent group represented by formula (25)". When q is 1, group (25) is a pyrrolidinediyl group, and when q is 2, group (25) is a piperidinediyl group.

[0158] A cyclic alkylene tertiary amino group having 2 nitrogen atoms and 2 to 5 carbon atoms is preferably of formula (26):

[0159]

[0160] It is a divalent group represented by (26) (where * represents the bond position and r represents 1 or 2). When r is 1, group (26) is an imidazolidinediyl group, and when r is 2, group (26) is a piperazinediyl group.

[0161] X ａ is X ｂ It may be the same as or different from X ａ is X ｂ It is the same group as X. In one embodiment of the present invention, X ａ and X ｂ Preferably, each is independently a cyclic alkylene tertiary amino group having 1 or 2 nitrogen atoms and 2 to 5 carbon atoms, more preferably independently a group (25) or a group (26), even more preferably independently a group (25), and particularly preferably both are groups (25) with q = 2 (i.e., piperidinediyl groups).

[0162] In another embodiment of the present invention, X ａ and X ｂ Preferably, each is independently group (24), group (25), or group (26), more preferably independently group (25) or group (26), even more preferably independently group (25), and particularly preferably both are group (25) with q = 2 (i.e., a piperidinediyl group).

[0163] R ７ａ and R ７ｂ Each of these independently represents an alkylene group having 1 to 8 carbon atoms or an oxydialkylene group having 2 to 8 carbon atoms. The oxydialkylene group having 2 to 8 carbon atoms is preferably an oxydimethylene group, an oxydiethylene group, or an oxydipropylene group, and more preferably an oxydiethylene group.

[0164] R ７ａ and R ７ｂ Preferably, each is an alkylene group having 1 to 8 carbon atoms independently, more preferably, each is an alkylene group having 1 to 4 carbon atoms independently, and even more preferably, both are ethylene groups.

[0165] The hydrogen atom at the far right in equation (6a) is X ａ It is bonded to the nitrogen atom in the middle, and the hydrogen atom at the far right of formula (6b) is X ｂ It is bonded to the nitrogen atom inside. For example, X ａ If the base is (24), then compound (6a) is X ａ The nitrogen atom inside contains a hydrogen atom and R ７ａ It is a compound having a structure in which X is bonded. For example, X ａ When (25) is the base, compound (6a) has hydrogen atoms bonded at the bond position marked with * and R at the bond position marked with **. ７ａ It is a compound having a structure in which X is bonded. For example, X ａ If the base is (26), then compound (6a) is X ａ A hydrogen atom is bonded to one of the nitrogen atoms, and R is bonded to the other nitrogen atom. ７ａ It is a compound having a structure in which these are bonded. The description of compound (6b) is the same as the description of compound (6a).

[0166] Below, R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , and R ７ｂ Preferred combinations are described. In preferred combinations, R １ａ and R １ｂ Each of these is an alkylene group with 1 to 4 carbon atoms, X ａ and X ｂ Each of these is independent of the base (24) (wherein * is as described above, R ３７ is an alkyl group having 1 to 6 carbon atoms. ), group (25) (in formula (25), * and ** are as described above, and q is 1 or 2), or group (26) (in formula (26), * is as described above, and r is 1 or 2), and R ７ａ and R ７ｂ These are, independently, alkylene groups with 1 to 8 carbon atoms.

[0167] In a more preferred combination, R １ａ and R １ｂThese are, independently, a methylene group, an ethylene group, a trimethylene group, and a propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), or a tetramethylene group, X ａ and X ｂ Each is independently base (25) (wherein formula (25), * and ** are as described above, and q is 1 or 2) or base (26) (wherein formula (26), * is as described above, and r is 1 or 2), and R ７ａ and R ７ｂ These are each an alkylene group with 1 to 4 carbon atoms, independently of each other.

[0168] In a more preferable combination, R １ａ and R １ｂ Both are ethylene groups, X ａ and X ｂ Both are base (25) (wherein * and ** are as described above, and q is 2), and R ７ａ and R ７ｂ Both are ethylene groups.

[0169] Next, we will explain the reaction in step 2b. When compound (6a) is the same as compound (6b), "reacting compound (1), compound (6a), and compound (6b)" means "reacting compound (1) with compound (6a)."

[0170] If compound (6a) is different from compound (6b), then "reacting compound (1), compound (6a), and compound (6b)" means reacting compound (1) with either compound (6a) or compound (6b), and then reacting the resulting reaction product with the other compound (6a) or compound (6b).

[0171] First, the reaction in step 2b when compound (6a) is the same as compound (6b) will be described. The reaction between compound (1) and compound (6a) is preferably carried out in an organic solvent. Only one organic solvent may be used, or two or more may be used in combination. Examples of organic solvents for the reaction include acetonitrile, acetone, methanol, ethanol, 2-propanol, chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and tetrahydrofuran (hereinafter sometimes abbreviated as "THF"). The organic solvent for the reaction is preferably acetonitrile.

[0172] When compound (6a) is the same as compound (6b), the ratio of organic solvent used in the reaction between compound (1) and compound (6a) is preferably 5 to 20 g, and more preferably 8 to 15 g, per 1 g of compound (1), from the viewpoint of dissolving the reactants and promoting the reaction.

[0173] When compound (6a) is the same as compound (6b), the amount ratio of compound (6a) used is preferably 3 to 10 mol, and more preferably 4 to 8 mol, per 1 mol of compound (1), from the viewpoint of promoting the reaction.

[0174] In the reaction between compound (1) and compound (6a), it is preferable to use an inorganic base. Only one inorganic base may be used, or two or more may be used in combination. The inorganic base for the reaction is preferably an alkali metal salt. Examples of alkali metal salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The inorganic base for the reaction is more preferably at least one selected from the group consisting of sodium carbonate and potassium carbonate, and even more preferably sodium carbonate. From the viewpoint of promoting the reaction, the ratio of the inorganic base used in the reaction is preferably 1.5 to 5.0 mol, more preferably 2.0 to 4.0 mol, per 1 mol of compound (1).

[0175] The reaction temperature between compound (1) and compound (6a) is preferably 20 to 60°C, and more preferably 40 to 50°C, from the viewpoint of promoting the reaction. The reaction time between compound (1) and compound (6a) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 2 to 24 hours.

[0176] After the reaction between compound (1) and compound (6a) is complete, it is preferable to add an organic solvent to the reaction mixture and remove insoluble matter by filtration. One organic solvent may be used alone, or two or more may be used in combination. Examples of organic solvents for this purpose include chloroform, dichloromethane, acetone, methanol, ethanol, 2-propanol, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF, among which chloroform and dichloromethane are preferred, and chloroform is more preferred. The amount ratio of the organic solvent used to remove insoluble matter is preferably 10 to 30 g, more preferably 15 to 20 g, per 1 g of compound (1).

[0177] After removing the insoluble matter as described above, the target compound (5) (in this case, the reaction product of compound (1) and compound (6a)) can be obtained by performing normal purification and recovery operations (for example, pH adjustment with an aqueous acid solution, washing with an organic solvent, pH adjustment with an aqueous inorganic base solution, extraction, and concentration).

[0178] Next, the reaction in step 2b when compound (6a) is different from compound (6b) will be described. Below, we will describe an embodiment in which compound (1) and compound (6a) are reacted, and the resulting reaction product of compound (1) and compound (6a) is reacted with compound (6b) (hereinafter abbreviated as "embodiment (6a-6b)"). Note that an embodiment in which compound (1) and compound (6b) are reacted, and the resulting reaction product of compound (1) and compound (6b) is reacted with compound (6a) (hereinafter abbreviated as "embodiment (6b-6a)" is also within the scope of the present invention. The description of embodiment (6b-6a) is the same as the description of embodiment (6a-6b) described later, except that "compound (6a)" is replaced with "compound (6b)" and "compound (6b)" is replaced with "compound (6a)".

[0179] The explanation of the reaction between compound (1) and compound (6a) when compound (6a) is different from compound (6b) is the same as the explanation of the reaction between compound (1) and compound (6a) when compound (6a) is the same as compound (6b), except for the ratio of compound (6a).

[0180] When compound (6a) is different from compound (6b), the amount ratio of compound (6a) used is preferably 0.3 to 1.5 mol, and more preferably 0.5 to 1.0 mol, per 1 mol of compound (1), from the viewpoint of promoting the reaction.

[0181] After the reaction between compound (1) and compound (6a) is complete, it is preferable to add an organic solvent to the reaction mixture and remove insoluble matter by filtration. This explanation is the same as the explanation above.

[0182] After removing the insoluble matter as described above, the reaction products of the target compounds (1) and (6a) can be obtained by performing normal purification and recovery operations (for example, pH adjustment with an aqueous acid solution, washing with an organic solvent, pH adjustment with an aqueous inorganic base solution, extraction, and concentration).

[0183] The reaction between the reaction product of compound (1) and compound (6a) and compound (6b) is preferably carried out in an organic solvent. The organic solvent may be used alone or in combination of two or more. Examples of organic solvents for the reaction include acetonitrile, acetone, methanol, ethanol, 2-propanol, chloroform, dichloromethane, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is preferably acetonitrile.

[0184] The ratio of the organic solvent used in the reaction between the reaction product of compound (1) and compound (6a) and compound (6b) is preferably 5 to 20 g, and more preferably 8 to 15 g, per 1 g of the reaction product of compound (1) and compound (6a), from the viewpoint of dissolving the reactants and promoting the reaction.

[0185] From the viewpoint of promoting the reaction, the amount ratio of compound (6b) used is preferably 0.5 to 5 mol, and more preferably 2 to 4 mol, per 1 mol of the reaction product of compound (1) and compound (6a).

[0186] In the reaction between the reaction product of compound (1) and compound (6a) and compound (6b), it is preferable to use an inorganic base. Only one inorganic base may be used, or two or more may be used in combination. The inorganic base for the reaction is preferably an alkali metal salt. Examples of alkali metal salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The inorganic base for the reaction is more preferably at least one selected from the group consisting of sodium carbonate and potassium carbonate, and even more preferably sodium carbonate. From the viewpoint of promoting the reaction, the ratio of the inorganic base used in the reaction is preferably 1.5 to 5.0 mol, more preferably 2.0 to 4.0 mol, per 1 mol of the reaction product of compound (1) and compound (6a).

[0187] The reaction temperature between the reaction product of compound (1) and compound (6a) and compound (6b) is preferably 20 to 60°C, and more preferably 40 to 50°C, from the viewpoint of promoting the reaction. The reaction time between the reaction product of compound (1) and compound (6a) and compound (6b) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 2 to 24 hours.

[0188] After the reaction between the reaction products of compound (1) and compound (6a) and compound (6b) is complete, it is preferable to add an organic solvent to the reaction mixture and remove insoluble matter by filtration. This explanation is the same as the explanation above.

[0189] After removing the insoluble matter as described above, the target compound (5) (in this case, the reaction product of compound (1), compound (6a), and compound (6b)) can be obtained by performing normal purification and recovery operations (for example, pH adjustment with an aqueous acid solution, washing with an organic solvent, pH adjustment with an aqueous inorganic base solution, extraction, and concentration).

[0190] <Method for Producing Ionic Lipids (7a)> The present invention provides a method for producing ionic lipids represented by the following formula (7a) (which may be abbreviated as "ionic lipids (7a)" in this specification). The definitions of the symbols in formula (7a) will be described later.

[0191]

[0192] The method for producing the ionic lipid (7a) of the present invention comprises the following steps 3a and 3b: step 3a, which involves obtaining compound (5) by the method for producing compound (5) of the present invention; and step 3b, which involves reacting compound (5) with a compound represented by the following formula (19a) and a compound represented by the following formula (19b) to obtain ionic lipid (7a). The definitions of the symbols in formulas (19a) and (19b) will be described later.

[0193]

[0194] R in equations (7a), (19a), and (19b) １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , and R ７ｂ The explanation is the same as the explanation in the above sections on <Method for producing compound (1)> and <Method for producing compound (5)>.

[0195] In equations (7a), (19a), and (19b), na and nb each independently represent either 0 or 1. “na is 0” means that O-Z in equations (7a) and (19a) is equal to 0. ａ -CO is absent, and R in equation (7a) ８ａ -CO and O-R ７ａ and are combined, and R in formula (19a) ８ａ -CO and X ２ａ This means that and are combined. "nb is 0" means that O-Z in equations (7a) and (19b) ｂ -CO is absent, and R in equation (7a) ８ｂ -CO and O-R ７ｂ and are combined, and R in formula (19b) ８ｂ -CO and X ２ｂ This means that and are joined together.

[0196] In formulas (7a), (19a), (19b), (20), (21a), (21b), (22), and (7b), Z ａ and Z ｂ Each of these independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, possessing at least one aromatic ring, and possibly having a heteroatom. In the following, the aromatic ring and the aromatic compound are referred to as "Z ａ and Z ｂ It is sometimes abbreviated as "fragrance ring".

[0197] Z ａ and Z ｂ The aromatic ring may be either an aromatic hydrocarbon ring or an aromatic heterocycle. Examples of aromatic hydrocarbon rings include benzene rings, naphthalene rings, and anthracene rings. Examples of aromatic heterocycles include imidazole rings, pyrazole rings, oxazole rings, isoxazole rings, thiazole rings, isothiazole rings, triazine rings, pyrrole rings, franthiophene rings, pyrimidine rings, pyridazine rings, pyrazine rings, pyridine rings, purine rings, pteridine rings, benzimidazole rings, indole rings, benzofuran rings, quinazoline rings, phthalazine rings, quinoline rings, isoquinoline rings, coumarin rings, chromone rings, benzodiazepine rings, phenoxazine rings, phenothiazine rings, and acridine rings. ａ and Z ｂ The aromatic ring is preferably an aromatic hydrocarbon ring, and more preferably a benzene ring.

[0198] Z ａ and Z ｂThe aromatic ring may be substituted with substituents, such as acyl groups having 2 to 4 carbon atoms, alkoxycarbonyl groups having 2 to 4 carbon atoms, carbamoyl groups having 2 to 4 carbon atoms, acyloxy groups having 2 to 4 carbon atoms, acylamino groups having 2 to 4 carbon atoms, alkoxycarbonylamino groups having 2 to 4 carbon atoms, halogen atoms (i.e., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkylsulfanyl groups having 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, arylsulfonyl groups having 6 to 10 carbon atoms, nitro groups, trifluoromethyl groups, cyano groups, alkyl groups having 1 to 4 carbon atoms, ureido groups, alkoxy groups having 1 to 4 carbon atoms, aryl groups having 6 to 10 carbon atoms, and aryloxy groups having 6 to 10 carbon atoms. Preferred examples of the substituents include acetyl group, methoxycarbonyl group, methylcarbamoyl group, acetoxy group, acetamide group, methoxycarbonylamino group, fluorine atom, chlorine atom, bromine atom, iodine atom, methylsulfanyl group, phenylsulfonyl group, nitro group, trifluoromethyl group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group, ureido group, methoxy group, ethoxy group, propoxy group, isopropoxy group, tert-butoxy group, phenyl group, and phenoxy group.

[0199] Z ａ and Z ｂ Preferably, each independently, is formula (27):

[0200]

[0201] (In formula (27), * represents the bond position with O in formula (7a), formula (19a), formula (19b), formula (20), formula (21a), formula (21b), formula (22), or formula (7b), ** represents the bond position with CO in formula (7a), formula (20), formula (19a), formula (19b), formula (21a), formula (21b), or formula (7b), s represents an integer from 0 to 3, t represents an integer from 0 to 3, u represents an integer from 0 to 4, and u R ３８Each of these independently represents a substituent.) It is a divalent group represented by ). Note that the above "s and t" are methylene groups (CH ２ ) represents the number, and "s or t is 0" means that there is no corresponding methylene group. Also, the aforementioned "u" is R ３８ This represents the number of R, and "u is 0" means that R ３８ This means that it does not exist.

[0202] s is preferably 0 or 1, more preferably 0. t is preferably an integer between 0 and 2, more preferably 1. u is preferably an integer between 0 and 2, more preferably 0.

[0203] R ３８Preferably, these are acyl groups having 2 to 4 carbon atoms, alkoxycarbonyl groups having 2 to 4 carbon atoms, carbamoyl groups having 2 to 4 carbon atoms, acyloxy groups having 2 to 4 carbon atoms, acylamino groups having 2 to 4 carbon atoms, alkoxycarbonylamino groups having 2 to 4 carbon atoms, halogen atoms (i.e., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkylsulfanyl groups having 1 to 4 carbon atoms, alkylsulfonyl groups having 1 to 4 carbon atoms, arylsulfonyl groups having 6 to 10 carbon atoms, nitro groups, trifluoromethyl groups, cyano groups, alkyl groups having 1 to 4 carbon atoms, ureido groups, alkoxy groups having 1 to 4 carbon atoms, aryl groups having 6 to 10 carbon atoms, or aryloxy groups having 6 to 10 carbon atoms. More preferably, an acetyl group, methoxycarbonyl group, methylcarbamoyl group, acetoxy group, acetamide group, methoxycarbonylamino group, halogen atom (i.e., fluorine atom, chlorine atom, bromine atom, iodine atom), methylsulfanyl group, phenylsulfonyl group, nitro group, trifluoromethyl group, cyano group, alkyl group having 1 to 4 carbon atoms (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group), ureido group, alkoxy group having 1 to 4 carbon atoms (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, tert-butoxy group), phenyl group, or phenoxy group. More preferably are halogen atoms (i.e., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), C1-C4 alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group, tert-butyl group), or C1-C4 alkoxy groups (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, tert-butoxy group), and particularly preferably halogen atoms (i.e., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms) or C1-C4 alkoxy groups (e.g., methoxy group, ethoxy group). ３８ If multiple R ３８ They may be the same or different from one another.

[0204] Z ａ is Z ｂ It may be the same as or different from Z, but preferably Z ａ is Z ｂIt is the same base as Z. ａ and Z ｂ Preferably, each is independently a base (27), more preferably independently a base (27) where s is 0 or 1, t is an integer from 0 to 2, and u is an integer from 0 to 2, and even more preferably both are bases (27) where s is 0, t is 1, and u is 0.

[0205] In formulas (7a), (19a), (19b), (7b), (23a), and (23b), R ８ａ and R ８ｂ These are, independently, monovalent groups as listed below. ８ａ and R ８ｂ These can be the same or different.

[0206] (i) A monovalent group having 10 to 50 carbon atoms having one carbonyl group and at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds (excluding monovalent groups containing residues of lipid-soluble vitamins having a hydroxyl group and residues of sterol derivatives having a hydroxyl group) (hereinafter sometimes abbreviated as "group (i)")

[0207] (ii) A monovalent group having 10 to 50 carbon atoms having at least two carbonyl groups (hereinafter sometimes abbreviated as "group (ii)" (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups)),

[0208] (iii) Formula (8): *-R ９ -X １ -R １０ (8) (In equation (8), * indicates the bonding position, R ９ X represents an alkylene group with 1 to 10 carbon atoms. １ R represents a carbamate bond, carbonate bond, or amide bond, and １０ represents an alkyl group having 1 to 25 carbon atoms, and R １０The monovalent group represented by (which may be abbreviated as "group (iii)") may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups.

[0209] (iv) Formula (9): *-R １１ -CO-O-R １２ (9) In equation (9), * represents the bonding position, R １１ R represents an alkylene group having 1 to 10 carbon atoms, and １２ This represents an alkyl group having 1 to 25 carbon atoms that is substituted with at least one halogen atom. ) A monovalent group represented by (hereinafter sometimes abbreviated as "group (iv)")

[0210] (v) Formula (10):

[0211]

[0212] (In equation (10), * represents the bond position, R １３ and R １４ Each of these independently represents an alkylene group with 1 to 10 carbon atoms, an alkenediyl group with 2 to 10 carbon atoms, or an alkynediyl group with 2 to 10 carbon atoms, R １５ ~R １７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ) (hereinafter sometimes abbreviated as "group (v)")

[0213] (vi) Formula (11):

[0214]

[0215] (In equation (11), * represents the bonding position, X ２ is a nitrogen atom or formula (12):

[0216]

[0217] (In equation (12), * represents R２１ This represents the bond position with, and ** is R ２２ or R ２３ This represents the bonding position with ( ). ) represents the trivalent group indicated by X ２ When R is a nitrogen atom, ２１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When is a trivalent group represented by formula (12), R ２１ R represents an alkylene group having 1 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When R is a nitrogen atom, ２２ and R ２３ Each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups, and X ２ When is a trivalent group represented by formula (12), R ２２ and R ２３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups.) A monovalent group represented by (hereinafter sometimes abbreviated as "group (vi)")

[0218] (vii) Formula (13):

[0219] (In formula (13), * represents the bond position, and R ２４ It consists of a hydrogen atom, a benzyl group, and *-Si(R １８ ) (Caution １９ ) (Caution ２０) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) represents a monovalent group represented by ) (hereinafter sometimes abbreviated as "group (vii)")

[0220] (viii) Formula (14):

[0221]

[0222] (In formula (14), * represents the bond position, and R ２６ and R ２７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ) (hereinafter sometimes abbreviated as "group (viiii)")

[0223] (ix) Formula (15):

[0224]

[0225] (In formula (15), * represents the bond position, and R ２８ is a hydrogen atom, a benzyl group, or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ) (hereinafter sometimes abbreviated as "group (ix)")

[0226] (x) Formula (16):

[0227]

[0228] (In formula (16), * represents the bonding position, R ２９ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３０ This represents an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or an alkynyl group having 2 to 30 carbon atoms.) A monovalent group represented by (hereinafter sometimes abbreviated as "group (x)")

[0229] (xi) Formula (17):

[0230]

[0231] (In formula (17), * represents the bond position, and R ３１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３２ and R ３３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms.) A monovalent group represented by (hereinafter sometimes abbreviated as "group (xi)")

[0232] (xi) Equation (18):

[0233]

[0234] (In formula (18), * represents the bond position, R ３４ R represents an alkylene group having 1 to 10 carbon atoms, and ３５ and R ３６ Each of these independently represents an alkyl group having 1 to 10 carbon atoms. ) A monovalent group represented by (sometimes abbreviated as "group (xii)")

[0235] (xiiii) A monovalent group which is an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond (hereinafter sometimes abbreviated as "group (xiiii)")

[0236] (xiv)R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ 'xiv' represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and 'p' represents an integer from 1 to 8. (Hereinafter, this may be abbreviated as "xiv").

[0237] The preferred group (i) is the following monovalent group: (i-1) Formula (28): *-R ３９ -CO-X ３ -R ４０ (28) (In equation (28), * indicates the bonding position, R ３９ R represents an alkylene group having 2 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ３９ R may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ４０ R represents an alkyl group having 1 to 40 carbon atoms, an alkenyl group having 2 to 40 carbon atoms, or an alkynyl group having 2 to 40 carbon atoms, and ４０ R may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ３９ and R ４０ At least one of them has at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds, and X ３ ) represents an oxygen atom, NH, or sulfur atom. ) A monovalent group with 10 to 50 carbon atoms (hereinafter sometimes abbreviated as "group (i-1)")

[0238] (i-2) Equation (29):

[0239]

[0240] (In formula (29), * represents the bond position, and R ４１R represents an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or a hydrocarbon ring group having 3 to 12 carbon atoms. ４１ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ４１ This may be substituted with substituents selected from the group consisting of alkoxy groups having 1 to 4 carbon atoms, heterocyclic groups having 3 to 14 members, and hydrocarbon ring groups having 3 to 12 carbon atoms.) A monovalent group having 50 or fewer carbon atoms represented by (hereinafter sometimes abbreviated as "group (i-2)").

[0241] In this specification, "R ３９ The phrase "may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms" means that R ３９ This means that the alkylene group, the alkenediyl group, and the alkynediyl group may each be independently substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ３９ Other expressions similar to "may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms" are also used, such as "R ３９ This has the same meaning as "may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms."

[0242] R in equation (28) ３９Preferably, the substituent is an alkylene group having 2 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, more preferably an alkylene group having 2 to 8 carbon atoms or an alkenediyl group having 2 to 8 carbon atoms, and even more preferably an alkylene group having 2 to 8 carbon atoms. In this specification, unless otherwise specified regarding substituents, "alkylene group," "alkenediyl group," "alkynediyl group," "alkyl group," "alkenyl group," and "alkynyl group" refer to unsubstituted groups.

[0243] R in equation (28) ４０ Preferably, the group is an alkyl group having 1 to 40 carbon atoms, an alkenyl group having 2 to 40 carbon atoms, or an alkynyl group having 2 to 40 carbon atoms; more preferably, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms; even more preferably, an alkenyl group having 2 to 20 carbon atoms or an alkynyl group having 2 to 20 carbon atoms; and particularly preferably, an alkenyl group having 2 to 20 carbon atoms.

[0244] R in equation (28) ３９ and R ４０ As described above, at least one of them has at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds. X in formula (28) ３ Preferably, it is an oxygen atom.

[0245] R in equation (29) ４１ Preferably, represents an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or a hydrocarbon ring group having 3 to 12 carbon atoms, and R ４１ It may be substituted with substituents selected from the group consisting of 3- to 14-membered heterocyclic groups and hydrocarbon ring groups having 3 to 12 carbon atoms.

[0246] R in equation (29) ４１The more preferably, the alkyl group is a C1-C20 alkyl group, a C2-C20 alkenyl group, a C2-C20 alkynyl group, or a C3-C12 hydrocarbon ring group, and the alkyl group may be substituted with a 3-C14 heterocyclic group.

[0247] R in equation (29) ４１ The C1-C20 alkyl group is more preferably a C1-C20 alkenyl group, a C2-C20 alkynyl group, or a cyclohexyl group, and the C1-C20 alkyl group may be substituted with a dithiolanyl group (e.g., 1,2-dithiolan-3-yl group).

[0248] R in equation (29) ４１ The alkyl group is particularly preferably an alkyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 20 carbon atoms, or a cyclohexyl group, and the alkyl group may be substituted with a dithiolanyl group (e.g., 1,2-dithiolan-3-yl group).

[0249] The preferred group (ii) is the monovalent group listed below: (ii-1) Formula (30): *-R ４２ -CO-X ４ -R ４３ (30) (In formula (30), * indicates the bonding position, R ４２ R represents an alkylene group having 2 to 9 carbon atoms, an alkenediyl group having 2 to 9 carbon atoms, or an alkynediyl group having 2 to 9 carbon atoms, and R ４２ R may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ４３ R represents an alkyl group having 7 to 45 carbon atoms, an alkenyl group having 7 to 45 carbon atoms, or an alkynyl group having 7 to 45 carbon atoms. ４３ At least one ethylene group or at least one trimethylene group in is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ４３X may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms, and X ４ ) represents an oxygen atom, NH, or sulfur atom. ) A monovalent group with 50 or fewer carbon atoms (hereinafter sometimes abbreviated as "group (iii-1)")

[0250] (ii-2) Formula (31): *-R ４４ -O-R ４５ (31) (In formula (31), * represents the bond position, and R ４４ R represents an alkylene group having 2 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms. ４４ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ４４ R may be substituted with substituents selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms, and R ４５ R represents an alkyl group having 3 to 30 carbon atoms, an alkenyl group having 4 to 30 carbon atoms, or an alkynyl group having 4 to 30 carbon atoms. ４５ At least two methylene groups are replaced by at least two carbonyl groups, and R ４５ At least one methylene group may be replaced by at least one ether bond.) A monovalent group having 10 to 50 carbon atoms represented by (hereinafter sometimes abbreviated as "group (ii-2)")

[0251] (ii-3) Formula (32):

[0252]

[0253] (In equation (32), * represents the bonding position, R ４６ and R ４７ Each of these independently represents an alkylene group having 3 to 10 carbon atoms, and R ４８ ~R ５０Each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, R ４８ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ４９ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ５０ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ４８ ~R ５０ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms.) A monovalent group having 50 or fewer carbon atoms represented by (hereinafter sometimes abbreviated as "group (ii-3)"), or (ii-4) formula (33):

[0254]

[0255] (In equation (33), * represents the bonding position, R ５１ R represents an alkylene group having 5 to 10 carbon atoms, and ５２ ~R ５４ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, R ５２ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ５３At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ５４ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ５２ ~R ５４ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms.) A monovalent group having 50 or fewer carbon atoms represented by (hereinafter sometimes abbreviated as "group (ii-4)").

[0256] X in equation (30) ４ is preferably an oxygen atom or NH, and more preferably an oxygen atom.

[0257] R in equation (30) ４２ Preferably, is an alkylene group having 2 to 9 carbon atoms, an alkenediyl group having 2 to 9 carbon atoms, or an alkinediyl group having 2 to 9 carbon atoms; more preferably, is an alkylene group having 2 to 9 carbon atoms or an alkenediyl group having 2 to 9 carbon atoms; even more preferably, is an alkylene group having 2 or 3 carbon atoms or an alkenediyl group having 2 or 3 carbon atoms; and particularly preferably, is an alkylene group having 2 or 3 carbon atoms.

[0258] In this specification, "R ４３ "At least one ethylene group or at least one trimethylene group in the compound is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds" means R ４３ At least one ethylene group or at least one trimethylene group in the alkyl group is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, or R ４３At least one ethylene group or at least one trimethylene group in the alkenyl is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, or R ４３ This means that at least one ethylene group or at least one trimethylene group in the alkynyl group is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds. ４３ Other expressions similar to "R" include "at least one ethylene group or at least one trimethylene group in the compound is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds." ４３ This is equivalent to saying that "at least one ethylene group or at least one trimethylene group in the compound is replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds."

[0259] R in equation (30) ４３ Preferably, (ii-1-1) equation (34):

[0260]

[0261] (In formula (34), * indicates the bonding position, and R ５５ and R ５６ Each of these independently represents an alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an alkynyl group having 2 to 17 carbon atoms, R ５５ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ５６ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ５５and R ５６ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ) A monovalent group represented by formula (ii-1-2) (35):

[0262]

[0263] (In formula (35), * indicates the bonding position, and R ５７ and R ５８ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, R ５７ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ５８ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ５７ and R ５８ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms.) A monovalent group represented by formula (ii-1-3) (36):

[0264]

[0265] (In formula (36), * represents the bonding position, and R ５９ ~R ６１ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, R ５９ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ６０At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ６１ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ５９ ~R ６１ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ) This is a monovalent group represented by .

[0266] In other words, group (30) is preferably a monovalent group having 50 or fewer carbon atoms represented by the following formula (30-34), a monovalent group having 50 or fewer carbon atoms represented by the following formula (30-35), or a monovalent group having 50 or fewer carbon atoms represented by the following formula (30-36) (the definitions of the symbols in the following formulas are as described above).

[0267]

[0268]

[0269]

[0270] R in equations (30-34) to (30-36) ４２ and X ４ The explanation is as described above. R in equations (34) and (30-34) ５５ and R ５６ Preferably, each is independently an alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an alkynyl group having 2 to 17 carbon atoms; more preferably, each is independently an alkyl group having 1 to 17 carbon atoms or an alkynyl group having 2 to 17 carbon atoms; and even more preferably, each is independently an alkyl group having 1 to 17 carbon atoms.

[0271] R in equations (35) and (30-35) ５７ and R５８ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably, each is independently an alkyl group having 1 to 10 carbon atoms.

[0272] R in equations (36) and (30-36) ５９ ~R ６１ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably, each is independently an alkyl group having 1 to 10 carbon atoms.

[0273] R in equation (31) ４４ Preferably, it is an alkylene group having 2 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, more preferably an alkylene group having 2 to 10 carbon atoms, and even more preferably an alkylene group having 2 or 3 carbon atoms.

[0274] R in equation (31) ４５ Preferably, equation (ii-2-1) (37):

[0275]

[0276] (In formula (37), * represents a bond position, Me represents a methyl group, and R ６２ and R ６３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, R ６２ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ６３ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ６２and R ６３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms.) A monovalent group represented by formula (ii-2-2) (38):

[0277]

[0278] (In formula (38), * indicates the bonding position, and R ６４ and R ６５ Each of these independently represents an alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an alkynyl group having 2 to 17 carbon atoms, R ６４ At least one ethylene group or at least one trimethylene group in R may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, ６５ At least one ethylene group or at least one trimethylene group in the compound may be replaced by at least one bond selected from the group consisting of ester bonds, amide bonds, carbamate bonds, and carbonate bonds, and R ６４ and R ６５ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms, hydroxyl groups, and hydrocarbon ring groups having 3 to 12 carbon atoms. ) is a monovalent group represented by .

[0279] In other words, group (31) is preferably a monovalent group having 50 or fewer carbon atoms represented by the following formula (31-37), or a monovalent group having 1 to 50 carbon atoms represented by the following formula (31-38) (the definitions of the symbols in the following formulas are as described above).

[0280]

[0281]

[0282] R in equations (31-37) and (31-38) ４４The explanation is as described above. In formulas (31-37), Me represents a methyl group, as described above. R in formulas (37) and (31-37) ６２ and R ６３ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably, each is independently an alkyl group having 1 to 10 carbon atoms.

[0283] R in equations (38) and (31-38) ６４ and R ６５ Preferably, each is independently an alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an alkynyl group having 2 to 17 carbon atoms; more preferably, each is independently an alkyl group having 1 to 17 carbon atoms; and even more preferably, each is independently an alkyl group having 1 to 10 carbon atoms.

[0284] R in equation (32) ４８ ~R ５０ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably an alkyl group having 1 to 10 carbon atoms.

[0285] R in equation (33) ５２ ~R ５４ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and more preferably, each is independently an alkyl group having 1 to 10 carbon atoms.

[0286] In formula (8), R ９ R represents an alkylene group with 1 to 10 carbon atoms. ９ This is preferably an alkylene group having 2 or 3 carbon atoms.

[0287] X in equation (8) １ Preferably, *-NH-CO-O-** (wherein * is R in formula (8)) ９ This represents the bonding position with R in equation (8), and ** is R１０ The bond position is represented by ), or *-O-CO-O-* (wherein * represents the bond position), and more preferably *-NH-CO-O-** (wherein * represents the bond position in formula (8) ９ This represents the bonding position with R in equation (8), and ** is R １０ This represents the bond position with ). R in equation (8) １０ Preferably, it is an alkyl group having 1 to 25 carbon atoms.

[0288] R in equation (9) １１ As mentioned above, R is an alkylene group having 1 to 10 carbon atoms. １２ Preferably, it is an alkyl group having 1 to 25 carbon atoms that is substituted with at least one fluorine atom.

[0289] R in equation (10) １３ and R １４ Preferably, each is an alkylene group having 1 to 10 carbon atoms. １５ ~R １７ Preferably, each independently comprises a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group.) More preferably, each independently represents a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group.) More preferably, each independently represents a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, R １９and R ２０ Both represent a methyl group.

[0290] X in equation (11) ２ The X in formula (11) is preferably group (12). ２ When is a nitrogen atom, R in formula (11) ２１ X in formula (11) is preferably an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and more preferably an alkylene group having 1 to 10 carbon atoms. ２ When is the base (12), R in equation (11) ２１ Preferably, it is an alkylene group having 1 to 10 carbon atoms.

[0291] X in equation (11) ２ When is a nitrogen atom or group (12), then R in formula (11) ２２ and R ２３ Preferably, each is independently an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a hydroxyl group. ２２ and R ２３ More preferably, each is an alkyl group having 1 to 10 carbon atoms.

[0292] R in equation (13) ２４ Preferably a hydrogen atom, a benzyl group, *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) More preferably a hydrogen atom, *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R１８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) More preferably a hydrogen atom, *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) More preferably *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ This represents an alkyl group having 1 to 9 carbon atoms.

[0293] R in equation (14) ２６ and R ２７ Preferably, each independently comprises a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group.) More preferably, each independently represents a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group.) More preferably, each independently represents a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, R １９ and R ２０ Both represent a methyl group.

[0294] R in equation (15) ２８ Preferably a hydrogen atom, a benzyl group, or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group. ) and more preferably a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, and R １９ and R ２０ Both represent a methyl group or a phenyl group.) More preferably a hydrogen atom or *-Si (R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ represents a tert-butyl group, R １９ and R ２０ Both represent a methyl group.

[0295] R in equation (16) ２９ R in formula (16) is preferably an alkylene group having 1 to 10 carbon atoms. ３０ Preferably, it is an alkyl group having 1 to 30 carbon atoms.

[0296] R in equation (17) ３１ R in formula (17) is preferably an alkylene group having 1 to 10 carbon atoms, and more preferably an alkylene group having 2 or 3 carbon atoms. ３２ and R ３３Preferably, each is independently an alkyl group having 2 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms, and more preferably, each is independently an alkenyl group having 2 to 10 carbon atoms.

[0297] R in equation (18) ３４ As mentioned above, R is an alkylene group having 1 to 10 carbon atoms. ３５ and R ３６ As mentioned above, each of these is an alkyl group having 1 to 10 carbon atoms, independently of the others.

[0298] The group (xiiii) is preferably a monovalent group having 1 to 30 carbon atoms in an alkyl group or 2 to 20 carbon atoms in an alkenyl group, wherein one ethylene group in the alkyl group may be replaced by one ester bond. In other words, the group (xiiii) is preferably a monovalent group having 1 to 30 carbon atoms in an alkyl group or 2 to 20 carbon atoms in an alkenyl group, wherein one ethylene group may be replaced by one ester bond. The group (xiiii) is more preferably a monovalent group derived from intermediate 13, intermediate 14, or oleic acid as described in the later examples, even more preferably a monovalent group derived from intermediate 13 or oleic acid as described in the later examples, and even more preferably a monovalent group derived from oleic acid. In this specification, “monovalent group derived from oleic acid” means a monovalent group having a structure obtained by removing a carboxyl group from oleic acid (i.e., a (Z)-8-heptadecenyl group). In this specification, "monovalent group derived from intermediate X" (X: an integer of 1 or more) means a monovalent group having a structure obtained by removing a carboxyl group from intermediate X.

[0299] The base (xiv) is, as mentioned above, R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ) represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p represents an integer from 1 to 8. p is preferably 2 or 3. The fat-soluble vitamin having a hydroxyl group is preferably tocopherol. The sterol derivative having a hydroxyl group is preferably cholesterol or cholestanol, and more preferably cholesterol.

[0300] R ８ａ and R ８ｂ Preferably, each is independently of the base (i-1) (base (28)), base (i-2) (base (29)), base (ii-1) (especially bases (30-34), base (30-36)), base (ii-4) (base (33)), base (iii) (base (8)), base (ix) (base (15)), base (xi) (base (17)), base (xiiii), or base (xiv).

[0301] In equations (19a) and (19b), X ２ａ and X ２ｂ Each of these independently represents a hydroxyl group or a halogen atom. Here, X ２ａ If it is a hydroxyl group, then -CO-X ２ａ represents a carboxyl group, X ２ｂ If it is a hydroxyl group, then -CO-X ２ｂ X represents a carboxyl group. ２ａ and X ２ｂ Preferably, each is independently a hydroxyl group or a chlorine atom, and more preferably, both are hydroxyl groups.

[0302] Below, R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ na, nb, Z ａ Z ｂ , R ８ａ , and R ８ｂ Preferred combinations are described. In preferred combinations, R １ａ and R １ｂ Each of these is an alkylene group with 1 to 4 carbon atoms, X ａ and Xｂ Each of these is independent of the base (24) (wherein * is as described above, R ３７ is an alkyl group having 1 to 6 carbon atoms. ), group (25) (wherein * and ** are as described above, and q is 1 or 2), or group (26) (wherein in formula (26) * is as described above, and r is 1 or 2), R ７ａ and R ７ｂ Each is an alkylene group having 1 to 8 carbon atoms, and na and nb are each independently 0 or 1, Z ａ and Z ｂ Preferably, each is independently of the base (27) (wherein * and ** are as described above, s is an integer from 0 to 3, t is an integer from 0 to 3, u is an integer from 0 to 4, and u R ３８ These are each independent substituents. ) and R ８ａ and R ８ｂ Each is independent of the other, Base (28) (wherein * is as described above, R ３９ R is an alkylene group having 2 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms. ４０ is an alkyl group having 1 to 40 carbon atoms, an alkenyl group having 2 to 40 carbon atoms, or an alkynyl group having 2 to 40 carbon atoms, and X ３ is an oxygen atom. ), group (29) (in formula (29), * is as described above, R ４１ R is an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or a hydrocarbon ring group having 3 to 12 carbon atoms, and R ４１ ) may be substituted with substituents selected from the group consisting of 3- to 14-membered heterocyclic groups and hydrocarbon ring groups having 3 to 12 carbon atoms. ), group (30-34) (wherein * is as described above, R ４２ X is an alkylene group having 2 to 9 carbon atoms, an alkenediyl group having 2 to 9 carbon atoms, or an alkynediyl group having 2 to 9 carbon atoms. ４is an oxygen atom or NH, and R ５５ and R ５６ Each of these is independently an alkyl group having 1 to 17 carbon atoms, an alkenyl group having 2 to 17 carbon atoms, or an alkynyl group having 2 to 17 carbon atoms. ), group (30-36) (In formula (30-36), * is as described above, R ４２ X is an alkylene group having 2 to 9 carbon atoms, an alkenediyl group having 2 to 9 carbon atoms, or an alkynediyl group having 2 to 9 carbon atoms. ４ is an oxygen atom or NH, and R ５９ ~R ６１ Each of these is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms. ), group (33) (in formula (33), * is as described above, R ５１ is an alkylene group having 5 to 10 carbon atoms, and R ５２ ~R ５４ Each of these is independently an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms. ), group (8) (In formula (8), * is as described above, R ９ X is an alkylene group having 1 to 10 carbon atoms. １ *-NH-CO-O-** (where * is R in equation (8)) ９ This is the bonding position with, and ** is R in equation (8). １０ It is the bonding position with ), or *-O-CO-O-* (where * is the bonding position), and R １０ is an alkyl group having 1 to 25 carbon atoms.), group (15) (in formula (15), * is as described above, and R ２８ is a hydrogen atom, a benzyl group, or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (In the above formula, * represents the bond position, R １８ is a tert-butyl group, and R １９ and R ２０Both are methyl or phenyl groups. ) ), group (17) (In formula (17), * is as described above, R ３１ is an alkylene group having 1 to 10 carbon atoms, and R ３２ and R ３３ Each is independently an alkyl group having 2 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms. ), a monovalent group which is an alkyl group having 1 to 30 carbon atoms or an alkenyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ (where p is a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p is an integer from 1 to 8.)

[0303] In a more preferred combination, R １ａ and R １ｂ These are, independently, a methylene group, an ethylene group, a trimethylene group, and a propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), or a tetramethylene group, X ａ and X ｂ Each is independently base (25) (wherein formula (25), * and ** are as described above, and q is 1 or 2) or base (26) (wherein formula (26), * is as described above, and r is 1 or 2), R ７ａ and R ７ｂ Each is an alkylene group with 1 to 4 carbon atoms, and na and nb are each independently 0 or 1, Z ａ and Z ｂ Each is independently of the base (27) (wherein * and ** are as described above, s is 0 or 1, t is an integer from 0 to 2, u is an integer from 0 to 2, and u is 0), and R ８ａ and R８ｂ Each is independent of the other, Base (28) (wherein * is as described above, R ３９ R is an alkylene group having 2 to 8 carbon atoms or an alkenediyl group having 2 to 8 carbon atoms, ４０ is an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, and X ３ is an oxygen atom. ), group (29) (in formula (29), * is as described above, R ４１ is an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or a hydrocarbon ring group having 3 to 12 carbon atoms, and the alkyl group may be substituted with a heterocyclic group having 3 to 14 members. ), group (30-34) (wherein * is as described above, R ４２ X is an alkylene group having 2 to 9 carbon atoms or an alkenediyl group having 2 to 9 carbon atoms, ４ is an oxygen atom, and R ５５ and R ５６ Each of these is independently an alkyl group having 1 to 17 carbon atoms or an alkynyl group having 2 to 17 carbon atoms. ), group (30-36) (in formula (30-36), * is as described above, R ４２ X is an alkylene group having 2 to 9 carbon atoms or an alkenediyl group having 2 to 9 carbon atoms, ４ is an oxygen atom, and R ５９ ~R ６１ Each of these is an alkyl group having 1 to 10 carbon atoms. ), group (33) (in formula (33), * is as described above, R ５１ is an alkylene group having 5 to 10 carbon atoms, and R ５２ ~R ５４ Each of these is an alkyl group having 1 to 10 carbon atoms. ), group (8) (in formula (8), * is as described above, R ９ X is an alkylene group having 1 to 10 carbon atoms. １ *-NH-CO-O-** (where * is R in equation (8)) ９ This is the bonding position with, and ** is R in equation (8).１０ This is the bonding position with R. １０ is an alkyl group having 1 to 25 carbon atoms.), group (15) (in formula (15), * is as described above, and R ２８ is a hydrogen atom or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * is the bond position, R １８ is a tert-butyl group, and R １９ and R ２０ Both are methyl or phenyl groups. ) ), group (17) (In formula (17), * is as described above, R ３１ is preferably an alkylene group having 1 to 10 carbon atoms, and R ３２ and R ３３ Each of these is independently an alkenyl group having 2 to 10 carbon atoms. ), a monovalent group which is an alkyl group having 1 to 30 carbon atoms or an alkenyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ (where p is a tocopherol residue, or a cholesterol or cholestanol residue, and p is an integer from 1 to 8.)

[0304] In a more preferable combination, R １ａ and R １ｂ Both are ethylene groups, X ａ and X ｂ Both are base (25) (wherein * and ** are as described above, and q is 2), R ７ａ and R ７ｂ Both are ethylene groups, and na and nb are independently 0 or 1, Z ａ and Z ｂEach is independently of the base (27) (wherein * and ** are as described above, s is 0, t is 1, and u is 0), and R ８ａ and R ８ｂ Each is independent of the other, Base (28) (wherein * is as described above, R ３９ R is an alkylene group having 2 to 8 carbon atoms. ４０ is preferably an alkenyl group having 2 to 20 carbon atoms, and X ３ is an oxygen atom. ), group (29) (in formula (29), * is as described above, R ４１ is an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an alkynyl group having 2 to 20 carbon atoms, or a cyclohexyl group, and the alkyl group may be substituted with a dithiolanyl group (e.g., 1,2-dithiolan-3-yl group). ) Group (30-34) (In formula (30-34), * is as described above, R ４２ X is an alkylene group having 2 or 3 carbon atoms. ４ is an oxygen atom, and R ５５ and R ５６ More preferably, each is an alkyl group having 1 to 17 carbon atoms. ), group (30-36) (wherein * is as described above, R ４２ X is an alkylene group having 2 or 3 carbon atoms. ４ is an oxygen atom, and R ５９ ~R ６１ Each of these is an alkyl group having 1 to 10 carbon atoms. ), group (33) (in formula (33), * is as described above, R ５１ is an alkylene group having 5 to 10 carbon atoms, and R ５２ ~R ５４ Each of these is an alkyl group having 1 to 10 carbon atoms. ), group (8) (in formula (8), * is as described above, R ９ X is an alkylene group having 2 or 3 carbon atoms. １ *-NH-CO-O-** (where * is R in equation (8)) ９is the bonding position with, and ** is R in formula (8) １０ is the bonding position with.) and R １０ is an alkyl group having 1 to 25 carbon atoms.), group (15) (in formula (15), * is as described above, and R ２８ is a hydrogen atom or *-Si(R １８ )(R １９ )(R ２０ )(in the above formula, * is the bonding position, R １８ is a tert-butyl group, and R １９ and R ２０ are both methyl groups.)), group (17) (in formula (17), * is as described above, R ３１ is an alkylene group having 2 or 3 carbon atoms, and R ３２ [[ID=2nd]]and R ３３ are each independently an alkenyl group having 2 to 10 carbon atoms.)), a monovalent group derived from intermediate 13, intermediate 14 or oleic acid described in the examples below, or R ８ｃ -CO-(CH ２ )) ｐ -group (in the above formula, R ８ｃ is a residue of tocopherol or a residue of cholesterol, and p is 2 or 3.).

[0305] Next, the reaction of step 3b will be described. When compound (19a) is the same as compound (19b), "reacting compound (5) with compound (19a) and compound (19b)" means "reacting compound (5) with compound (19a)".

[0306] When compound (19a) is different from compound (19b), "reacting compound (5) with compound (19a) and compound (19b)" means reacting compound (1) with either compound (19a) or compound (19b), and reacting the resulting reaction product with the remaining one of compound (19a) or compound (19b).

[0307] First, the reaction in step 3b when compound (19a) is the same as compound (19b) will be described. The reaction between compound (5) and compound (19a) is preferably carried out in an organic solvent. Only one organic solvent may be used, or two or more may be used in combination. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is at least one selected from the group consisting of chloroform and dichloromethane, and more preferably dichloromethane.

[0308] When compound (19a) is the same as compound (19b), the ratio of organic solvents used in the reaction between compound (5) and compound (19a) is preferably 5 to 100 g, more preferably 10 to 50 g, per 1 g of compound (5), from the viewpoint of dissolving the reactants and promoting the reaction.

[0309] When compound (19a) is the same as compound (19b), the amount ratio of compound (19a) used is preferably 1 to 10 mol, and more preferably 2 to 5 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0310] The reaction between compound (5) and compound (19a) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and 4-dimethylaminopyridine (hereinafter sometimes abbreviated as "DMAP"). Among these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0311] When a base catalyst or an acid catalyst is used in the reaction between compound (5) and compound (19a), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0312] To promote the reaction between compound (5) and compound (19a), it is preferable to use a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter sometimes abbreviated as "EDC hydrochloride"). Among these, EDC hydrochloride is preferred.

[0313] When a condensing agent is used in the reaction between compound (5) and compound (19a), the amount ratio of the condensing agent is preferably 1 to 10 mol, and more preferably 2 to 6 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0314] The reaction temperature between compound (5) and compound (19a) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between compound (5) and compound (19a) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0315] After the reaction is complete, the desired ionic lipid (7a) (in this case, the reaction product of compound (5) and compound (19b)) can be obtained by performing normal purification and recovery operations (e.g., washing with water, concentration, and silica gel chromatography).

[0316] Next, the reaction in step 3b when compound (19a) is different from compound (19b) will be described. Below, we will describe an embodiment in which compound (5) and compound (19a) are reacted, and the resulting reaction product of compound (5) and compound (19a) is reacted with compound (19b) (hereinafter abbreviated as "embodiment (19a-19b)"). Note that an embodiment in which compound (5) and compound (19b) are reacted, and the resulting reaction product of compound (5) and compound (19b) is reacted with compound (19a) (hereinafter abbreviated as "embodiment (19b-19a)" is also within the scope of the present invention. The description of embodiment (19b-19a) is the same as the description of embodiment (19a-19b) described later, except that "compound (19a)" is replaced with "compound (19b)" and "compound (19b)" is replaced with "compound (19a)".

[0317] The explanation of the reaction between compound (5) and compound (19a) when compound (19a) is different from compound (19b) is the same as the explanation of the reaction between compound (5) and compound (19a) when compound (19a) is the same as compound (19b), except for the ratio of compound (19a).

[0318] When compound (19a) is different from compound (19b), the amount ratio of compound (19a) used is preferably 0.3 to 1.5 mol, and more preferably 0.5 to 1.0 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0319] After the reaction is complete, the reaction products of the target compounds (5) and (19a) can be obtained by performing normal purification and recovery operations (e.g., washing with water, concentration, and silica gel chromatography).

[0320] The reaction between the reaction product of compound (5) and compound (19a) and compound (19b) is preferably carried out in an organic solvent. One organic solvent may be used alone, or two or more may be used in combination. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is preferably at least one selected from the group consisting of chloroform and dichloromethane, and more preferably dichloromethane.

[0321] The ratio of organic solvent used in the reaction between the reaction product of compound (5) and compound (19a) and compound (19b) is preferably 5 to 100 g, and more preferably 10 to 50 g, per 1 g of the reaction product of compound (5) and compound (19a), from the viewpoint of dissolving the reactants and promoting the reaction.

[0322] From the viewpoint of promoting the reaction, the amount ratio of compound (19b) used is preferably 0.5 to 5 mol, and more preferably 2 to 4 mol, per 1 mol of the reaction product of compound (5) and compound (19a).

[0323] The reaction between the reaction product of compound (5) and compound (19a) and compound (19b) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and DMAP. Of these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0324] When a base catalyst or an acid catalyst is used in the reaction of the reaction product of compound (5) and compound (19a) with compound (19b), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of the reaction product of compound (5) and compound (19a), from the viewpoint of promoting the reaction.

[0325] It is preferable to use a condensing agent to promote the reaction between the reaction product of compound (5) and compound (19a) and compound (19b). Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and EDC hydrochloride. Among these, EDC hydrochloride is preferred.

[0326] When a condensing agent is used in the reaction between the reaction product of compound (5) and compound (19a) and compound (19b), the amount ratio of the condensing agent is preferably 1 to 10 mol, more preferably 2 to 6 mol, per 1 mol of the reaction product of compound (5) and compound (19a), from the viewpoint of promoting the reaction.

[0327] The reaction temperature between the reaction product of compound (5) and compound (19a) and compound (19b) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between the reaction product of compound (5) and compound (19a) and compound (19b) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0328] After the reaction is completed, ordinary purification and recovery operations (for example, washing with water, concentration, and silica gel chromatography) are performed to obtain the target ionic lipid (7a) (in this case, the reaction product of compound (5), compound (19a), and compound (19b)).

[0329] <Method for Producing Compound (20)> The present invention provides a method for producing a compound represented by the following formula (20) (which may be abbreviated as "compound (20)" in this specification). The definitions of the symbols in formula (20) will be described later.

[0330]

[0331] The method for producing compound (20) of the present invention includes the following steps 4a to 4c: Step 4a of obtaining compound (5) by the method for producing compound (5) of the present invention, Step 4b of reacting compound (5) with a compound represented by the following formula (21a) and a compound represented by the following formula (21b) to obtain a compound represented by the following formula (22), and Step 4c of deprotecting the compound represented by the following formula (22) to obtain compound (20). The definitions of the symbols in formula (21a), formula (21b), and formula (22) will be described later.

[0332]

[0333]

[0334] The descriptions of R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ , Z ａ , and Z ｂ are the same as the descriptions in the above <Method for Producing Compound (1)>, <Method for Producing Compound (5)>, and <Method for Producing Ionic Lipid (7a)>.

[0335] The Pr １ and Pr ２Each of these independently represents a protecting group for the hydroxyl group. Examples of hydroxyl group protecting groups include ether-based protecting groups, acetal-based protecting groups, silyl ether-based protecting groups, and acyl-based protecting groups. Protecting groups that can be removed under acidic conditions are preferred. Specific examples of hydroxyl group protecting groups include tetrahydropyran-2-yl group, methoxymethyl group, methoxyethoxyethyl group, trityl group, tert-butyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, and tert-butyldiphenylsilyl group. The hydroxyl group protecting group is preferably tetrahydropyran-2-yl group, methoxymethyl group, methoxyethoxyethyl group, or trityl group, tert-butyl group, and more preferably tetrahydropyran-2-yl group.

[0336] Below, R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ Z ａ Z ｂ , Pr １ , and Pr ２ Preferred combinations are described. In preferred combinations, R １ａ and R １ｂ Each of these is an alkylene group with 1 to 4 carbon atoms, X ａ and X ｂ Each of these is independent of the base (24) (wherein * is as described above, R ３７ is an alkyl group having 1 to 6 carbon atoms. ), group (25) (wherein * and ** are as described above, and q is 1 or 2), or group (26) (wherein in formula (26) * is as described above, and r is 1 or 2), R ７ａ and R ７ｂ These are each an alkylene group with 1 to 8 carbon atoms, Z ａ and Z ｂPreferably, each is independently of the base (27) (wherein * and ** are as described above, s is an integer from 0 to 3, t is an integer from 0 to 3, u is an integer from 0 to 4, and u R ３８ These are each an independent substituent. ) and Pr １ and Pr ２ These are, independently, a tetrahydropyran-2-yl group, a methoxymethyl group, a methoxyethoxyethyl group, or a trityl group or a tert-butyl group.

[0337] In a more preferred combination, R １ａ and R １ｂ These are, independently, a methylene group, an ethylene group, a trimethylene group, and a propylene group (-CH(CH ３ )CH ２ -ien-CH ２ CH (CH ３ )-), or a tetramethylene group, X ａ and X ｂ Each is independently base (25) (wherein formula (25), * and ** are as described above, and q is 1 or 2) or base (26) (wherein formula (26), * is as described above, and r is 1 or 2), R ７ａ and R ７ｂ These are each an alkylene group with 1 to 4 carbon atoms, Z ａ and Z ｂ Each is independently of the base (27) (wherein * and ** are as described above, s is 0 or 1, t is an integer between 0 and 2, u is an integer between 0 and 2, and u is 0), and Pr １ and Pr ２ These are, independently, a tetrahydropyran-2-yl group, a methoxymethyl group, a methoxyethoxyethyl group, or a trityl group or a tert-butyl group.

[0338] In a more preferable combination, R １ａ and R １ｂ Both are ethylene groups, X ａ and X ｂBoth are base (25) (wherein * and ** are as described above, and q is 2), R ７ａ and R ７ｂ Both are ethylene groups, Z ａ and Z ｂ Each is independently of the base (27) (wherein * and ** are as described above, s is 0, t is 1, and u is 0), and Pr １ and Pr ２ Each of these is independently a tetrahydropyran-2-yl group.

[0339] Next, we will explain the reaction in step 4b. When compound (21a) is the same as compound (21b), "reacting compound (5), compound (21a), and compound (21b)" means "reacting compound (5) with compound (21a)."

[0340] If compound (21a) is different from compound (21b), then "reacting compound (5), compound (21a), and compound (21b)" means reacting compound (1) with either compound (21a) or compound (21b), and then reacting the resulting reaction product with the other of compound (21a) or compound (21b).

[0341] First, the reaction in step 4b when compound (21a) is the same as compound (21b) will be described. The reaction between compound (5) and compound (21a) is preferably carried out in an organic solvent. Only one organic solvent may be used, or two or more may be used in combination. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is at least one selected from the group consisting of chloroform and dichloromethane, and is more preferably chloroform.

[0342] When compound (21a) is the same as compound (21b), the ratio of organic solvents used in the reaction between compound (5) and compound (21a) is preferably 5 to 100 g, more preferably 10 to 50 g, per 1 g of compound (5), from the viewpoint of dissolving the reactants and promoting the reaction.

[0343] When compound (21a) is the same as compound (21b), the amount ratio of compound (21a) used is preferably 1 to 10 mol, more preferably 2 to 5 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0344] The reaction between compound (5) and compound (21a) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and DMAP. Of these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0345] When a base catalyst or an acid catalyst is used in the reaction between compound (5) and compound (21a), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0346] To promote the reaction between compound (5) and compound (21a), it is preferable to use a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and EDC hydrochloride. Among these, EDC hydrochloride is preferred.

[0347] When a condensing agent is used in the reaction between compound (5) and compound (21a), the amount ratio of the condensing agent is preferably 1 to 10 mol, and more preferably 2 to 6 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0348] The reaction temperature between compound (5) and compound (21a) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between compound (5) and compound (21a) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0349] After the reaction is complete, normal purification and recovery operations (e.g., washing with water, dehydration with sodium sulfate, removal of sodium sulfate, and concentration) can be performed to obtain the target compound (22) (in this case, the reaction product of compound (5) and compound (21a)).

[0350] Next, the reaction in step 4b when compound (21a) is different from compound (21b) will be described. Below, we will describe an embodiment in which compound (5) and compound (21a) are reacted, and the resulting reaction product of compound (5) and compound (21a) is reacted with compound (21b) (hereinafter sometimes abbreviated as "embodiment (21b-21a)"). Note that the embodiment in which compound (5) and compound (21b) are reacted, and the resulting reaction product of compound (5) and compound (21b) is reacted with compound (21a) (hereinafter sometimes abbreviated as "embodiment (21b-21a)") is also within the scope of the present invention. The description of embodiment (21b-21a) is the same as the description of embodiment (21a-21b) described later, except that "compound (21a)" is replaced with "compound (21b)" and "compound (21b)" is replaced with "compound (21a)".

[0351] The explanation of the reaction between compound (5) and compound (21a) when compound (21a) is different from compound (21b) is the same as the explanation of the reaction between compound (5) and compound (21a) when compound (21a) is the same as compound (21b), except for the ratio of compounds (21a).

[0352] When compound (21a) is different from compound (21b), the amount ratio of compound (21a) used is preferably 0.3 to 1.5 mol, and more preferably 0.5 to 1.0 mol, per 1 mol of compound (5), from the viewpoint of promoting the reaction.

[0353] After the reaction is complete, the reaction products of the target compounds (5) and (21a) can be obtained by performing normal purification and recovery operations (e.g., washing with water, dehydration with sodium sulfate, removal of sodium sulfate, and concentration).

[0354] The reaction between the reaction product of compound (5) and compound (21a) and compound (21b) is preferably carried out in an organic solvent. One organic solvent may be used alone, or two or more may be used in combination. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is preferably at least one selected from the group consisting of chloroform and dichloromethane, and more preferably chloroform.

[0355] The ratio of the organic solvent used in the reaction between compound (5) and compound (21a) and compound (21b) is preferably 5 to 100 g, and more preferably 10 to 50 g, per 1 g of the reaction product of compound (5) and compound (21a), from the viewpoint of dissolving the reactants and promoting the reaction.

[0356] From the viewpoint of promoting the reaction, the amount ratio of compound (21b) used is preferably 0.5 to 5 mol, and more preferably 2 to 4 mol, per 1 mol of the reaction product of compound (5) and compound (21a).

[0357] The reaction between the reaction product of compound (5) and compound (21a) and compound (21b) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and DMAP. Of these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0358] When a base catalyst or an acid catalyst is used in the reaction of the reaction product of compound (5) and compound (21a) with compound (21b), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of the reaction product of compound (5) and compound (21a), from the viewpoint of promoting the reaction.

[0359] It is preferable to use a condensing agent to promote the reaction between the reaction product of compound (5) and compound (21a) and compound (21b). Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and EDC hydrochloride. Among these, EDC hydrochloride is preferred.

[0360] When a condensing agent is used in the reaction between the reaction product of compound (5) and compound (21a) and compound (21b), the amount ratio of the condensing agent is preferably 1 to 10 mol, more preferably 2 to 6 mol, per 1 mol of the reaction product of compound (5) and compound (21a), from the viewpoint of promoting the reaction.

[0361] The reaction temperature between the reaction product of compound (5) and compound (21a) and compound (21b) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between the reaction product of compound (5) and compound (21a) and compound (21b) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0362] After the reaction is complete, normal purification and recovery operations (e.g., washing with water, dehydration with sodium sulfate, removal of sodium sulfate, and concentration) can be performed to obtain the target compound (22) (in this case, the reaction product of compound (5), compound (21a), and compound (21b)).

[0363] Next, step 4c will be explained. Step 4c is the deprotection of compound (22) (i.e., the protecting group Pr １ and Pr ２This is the removal of the protecting group. The deprotection of compounds is well known to those skilled in the art and can be carried out appropriately depending on the type of protecting group used. For example, the removal of the tetrahydropyran-2-yl group can be done by using an acid (e.g., p-toluenesulfonic acid monohydrate).

[0364] After deprotection in step 4c), the target compound (20) can be obtained by performing normal purification and recovery operations (e.g., neutralization, washing with water, dehydration with sodium sulfate, removal of sodium sulfate, and crystallization).

[0365] <Method for Producing Ionic Lipids (7b)> The present invention provides a method for producing ionic lipids represented by the following formula (7b) (which may be abbreviated as "ionic lipids (7b)" in this specification). The definitions of the symbols in formula (7b) will be described later.

[0366]

[0367] The method for producing the ionic lipid (7b) of the present invention comprises the following steps 5a and 5b: step 5a, obtaining compound (20) by the method for producing compound (20) of the present invention; and step 5b, reacting compound (20) with a compound represented by the following formula (23a) and a compound represented by the following formula (23b) to obtain ionic lipid (7b). The definitions of the symbols in formulas (23a) and (23b) will be described later.

[0368]

[0369] R in equations (23a) and (23b) ８ａ and R ８ｂ The explanation is the same as the explanation in the above-mentioned <Method for producing ionic lipids (7a)>.

[0370] In equations (23a) and (23b), X ４ａ and X ４ｂ Each of these independently represents a hydroxyl group or a halogen atom. Here, X ４ａ If it is a hydroxyl group, then -CO-X ４ａ represents a carboxyl group, X ４ｂ If it is a hydroxyl group, then -CO-X ４ｂ X represents a carboxyl group.４ａ and X ４ｂ is preferably, each independently, a hydroxy group or a chlorine atom, and more preferably, both are hydroxy groups.

[0371] “Preferred combinations of R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ , Z ａ , Z ｂ , R ８ａ , and R ８ｂ and the like” is the same as the description of “Preferred combinations of R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ , na, nb, Z ａ , Z ｂ , R ８ａ , and R ８ｂ and the like” in the description of <Method for Producing Ionic Lipid (7b)>, except for excluding na and nb.

[0372] Next, the reaction in Step 5b will be described. When Compound (23a) is the same as Compound (23b), “reacting Compound (20) with Compound (23a) and Compound (23b)” means “reacting Compound (20) with Compound (23a)”.

[0373] When Compound (23a) is different from Compound (23b), “reacting Compound (20) with Compound (23a) and Compound (23b)” means reacting Compound (1) with either one of Compound (23a) or Compound (23b), and then reacting the resulting reaction product with the remaining one of Compound (23a) or Compound (23b).

[0374] First, the reaction in step 5b when compound (23a) is the same as compound (23b) will be described. The reaction between compound (20) and compound (23a) is preferably carried out in an organic solvent. Only one organic solvent may be used, or two or more may be used in combination. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is preferably at least one selected from the group consisting of chloroform and dichloromethane, and more preferably chloroform.

[0375] When compound (23a) is the same as compound (23b), the ratio of organic solvents used in the reaction between compound (20) and compound (23a) is preferably 5 to 100 g, more preferably 10 to 50 g, per 1 g of compound (20), from the viewpoint of dissolving the reactants and promoting the reaction.

[0376] When compound (23a) is the same as compound (23b), the amount ratio of compound (23a) used is preferably 1 to 10 mol, and more preferably 2 to 5 mol, per 1 mol of compound (20), from the viewpoint of promoting the reaction.

[0377] The reaction between compound (20) and compound (23a) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and DMAP. Of these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0378] When a base catalyst or an acid catalyst is used in the reaction between compound (20) and compound (23a), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of compound (20), from the viewpoint of promoting the reaction.

[0379] To promote the reaction between compound (20) and compound (23a), it is preferable to use a condensing agent. Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and EDC hydrochloride. Among these, EDC hydrochloride is preferred.

[0380] When a condensing agent is used in the reaction between compound (20) and compound (23a), the amount ratio of the condensing agent is preferably 1 to 10 mol, and more preferably 2 to 6 mol, per 1 mol of compound (20), from the viewpoint of promoting the reaction.

[0381] The reaction temperature between compound (20) and compound (23a) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between compound (20) and compound (23a) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0382] After the reaction is complete, the desired ionic lipid (7b) (in this case, the reaction product of compound (20) and compound (23a)) can be obtained by performing normal purification and recovery operations (e.g., washing with water, concentration, and silica gel chromatography).

[0383] Next, the reaction in step 5b when compound (23a) is different from compound (23b) will be described. Below, a mode in which compound (20) and compound (23a) are reacted, and the resulting reaction product of compound (20) and compound (23a) is reacted with compound (23b) (hereinafter abbreviated as "mode (23b-23a)") will be described. Note that a mode in which compound (20) and compound (23b) are reacted, and the resulting reaction product of compound (20) and compound (23b) is reacted with compound (23a) (hereinafter abbreviated as "mode (23b-23a)") is also within the scope of the present invention. The description of mode (23b-23a) is the same as the description of mode (23a-23b) described later, except that "compound (23a)" is replaced with "compound (23b)" and "compound (23b)" is replaced with "compound (23a)".

[0384] The explanation of the reaction between compound (20) and compound (23a) when compound (23a) is different from compound (23b) is the same as the explanation of the reaction between compound (20) and compound (23a) when compound (23a) is the same as compound (23b), except for the ratio of compound (23a).

[0385] When compound (23a) is different from compound (23b), the amount ratio of compound (23a) used is preferably 0.3 to 1.5 mol, and more preferably 0.5 to 1.0 mol, per 1 mol of compound (20), from the viewpoint of promoting the reaction.

[0386] After the reaction is complete, the reaction products of the target compounds (20) and (23a) can be obtained by performing normal purification and recovery operations (e.g., washing with water, concentration, and silica gel chromatography).

[0387] The reaction between the reaction product of compound (20) and compound (23a) and compound (23b) is preferably carried out in an organic solvent. The organic solvent may be used alone or in combination of two or more. Examples of organic solvents for the reaction include chloroform, dichloromethane, acetone, carbon tetrachloride, ethyl acetate, tert-butyl methyl ether, toluene, and THF. The organic solvent for the reaction is preferably at least one selected from the group consisting of chloroform and dichloromethane, and more preferably chloroform.

[0388] The ratio of the organic solvent used in the reaction between compound (20) and compound (23a) and compound (23b) is preferably 5 to 100 g, and more preferably 10 to 50 g, per 1 g of the reaction product of compound (20) and compound (23a), from the viewpoint of dissolving the reactants and promoting the reaction.

[0389] From the viewpoint of promoting the reaction, the amount ratio of compound (23b) used is preferably 0.5 to 5 mol, and more preferably 2 to 4 mol, per 1 mol of the reaction product of compound (20) and compound (23a).

[0390] The reaction between the reaction product of compound (20) and compound (23a) and compound (23b) may be carried out without a catalyst, but it is preferable to use a base catalyst or an acid catalyst to accelerate the reaction. Examples of base catalysts include potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, and DMAP. Of these, DMAP is preferred. Examples of acid catalysts include p-toluenesulfonic acid and methanesulfonic acid.

[0391] When a base catalyst or an acid catalyst is used in the reaction of the reaction product of compound (20) and compound (23a) with compound (23b), the ratio of the base catalyst or acid catalyst is preferably 0.05 to 3 mol, and more preferably 0.1 to 1 mol, per 1 mol of the reaction product of compound (20) and compound (23a), from the viewpoint of promoting the reaction.

[0392] It is preferable to use a condensing agent to promote the reaction between the reaction product of compound (20) and compound (23a) and compound (23b). Examples of condensing agents include dicyclohexylcarbodiimide, diisopropylcarbodiimide, and EDC hydrochloride. Among these, EDC hydrochloride is preferred.

[0393] When a condensing agent is used in the reaction between the reaction product of compound (20) and compound (23a) and compound (23b), the amount ratio of the condensing agent is preferably 1 to 10 mol, and more preferably 2 to 6 mol, per 1 mol of the reaction product of compound (20) and compound (23a), from the viewpoint of promoting the reaction.

[0394] The reaction temperature between the reaction product of compound (20) and compound (23a) and compound (23b) is preferably 0 to 80°C, and more preferably 10 to 50°C, from the viewpoint of promoting the reaction. The reaction time between the reaction product of compound (20) and compound (23a) and compound (23b) is not particularly limited, but is preferably 1 to 48 hours, and more preferably 1 to 24 hours.

[0395] After the reaction is complete, normal purification and recovery operations (e.g., washing with water, concentration, and silica gel chromatography) can be performed to obtain the target ionic lipid (7b) (in this case, the reaction product of compound (20), compound (23a), and compound (23b)).

[0396] The following describes embodiments of the present invention in more detail, but the present invention is not limited to these embodiments.

[0397] The meanings of the abbreviations used in the examples are as follows: DHP: 3,4-dihydro-2H-pyran DMAP: 4-dimethylaminopyridine DSC: N,N'-disuccinimidyl carbonate EDC hydrochloride: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride TBAF: tetra-n-butylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBDPS-Cl: tert-butyldiphenylsilyl chloride TBS: tert-butyldimethylsilyl TBS-Cl: tert-butyldimethylsilyl chloride THF: tetrahydrofuran THP: tetrahydropyran-2-yl

[0398] [Example 1] <Synthesis of bis[2-(p-toluenesulfonyloxy)ethyl]disulfide> To 20.0 g of a 50% by weight aqueous solution of 2-hydroxyethyl disulfide (64.8 mmol of 2-hydroxyethyl disulfide), an aqueous solution of potassium carbonate (53.8 g of potassium carbonate (389.0 mmol) in 200 g of deionized water) and a chloroform solution of triethylamine (3.3 g of triethylamine (32.4 mmol) in 200 g of chloroform) were added, respectively. Then, 49.4 g (259.3 mmol) of p-toluenesulfonyl chloride was added, and the reactants were reacted in a two-phase system at 25°C for 16 hours.

[0399] The lower organic phase was recovered from the two-phase system, and potassium carbonate aqueous solution (26.9 g (194.5 mmol) of potassium carbonate in 500 g of deionized water) was added to the recovered organic phase. The resulting mixture was stirred at 25°C for 2 hours. The mixture was allowed to stand, the lower organic phase was recovered, and the recovered organic phase was washed twice with 200 g of 5 wt% sodium dihydrogen phosphate aqueous solution and once with 200 g of 20 wt% saline solution, and then concentrated using an evaporator.

[0400] 50 g of ethanol was added to the obtained concentrate, and the mixture was stirred at 25°C for 30 minutes. The resulting crystals were collected by filtration and vacuum-dried to obtain 27.0 g of bis[2-(p-toluenesulfonyloxy)ethyl] disulfide (yield 90 mol% / 2-hydroxyethyl disulfide).

[0401] <Bis[2-(p-toluenesulfonyloxy)ethyl] disulfide １ H-NMR (400MHz, CDCl ３ )> δ: 2.46 (s, 6H), 2.83-2.86 (t, 4H), 4.19-4.23 (t, 4H), 7.36-7.38 (d, 4H), 7.79-7.81 (d, 4H)

[0402] [Example 2] <Synthesis of bis[2-(4-tert-butylbenzenesulfonyloxy)ethyl]disulfide> 20.0 g of a 50% by weight aqueous solution of 2-hydroxyethyl disulfide (64.8 mmol of 2-hydroxyethyl disulfide) was mixed with an aqueous solution of potassium carbonate (53.8 g of potassium carbonate (389.0 mmol) in 200 g of deionized water) and a chloroform solution of triethylamine (3.3 g of triethylamine (32.4 mmol) in 200 g of chloroform). Then, 60.3 g (259.3 mmol) of 4-tert-butylbenzenesulfonyl chloride was added, and the reaction mixture was reacted in a two-phase system at 25°C for 24 hours.

[0403] After the reaction, the mixture was purified in the same manner as in Example 1 to obtain 24.5 g of bis[2-(4-tert-butylbenzenesulfonyloxy)ethyl] disulfide (yield 92 mol% / 2-hydroxyethyl disulfide).

[0404] <Bis[2-(4-tert-butylbenzenesulfonyloxy)ethyl] disulfide １ H-NMR (400MHz, CDCl ３ )> δ: 1.37 (s, 18H), 2.83-2.86 (t, 4H), 4.19-4.23 (t, 4H), 7.62-7.64 (d, 4H), 7.95-7.97 (d, 4H)

[0405] [Example 3] <Synthesis of bis[2-(2-mesitylenesulfonyloxy)ethyl]disulfide> 20.0 g of a 50% by weight aqueous solution of 2-hydroxyethyl disulfide (64.8 mmol of 2-hydroxyethyl disulfide) was mixed with an aqueous solution of potassium carbonate (53.8 g of potassium carbonate (389.0 mmol) in 200 g of deionized water) and a chloroform solution of triethylamine (3.3 g of triethylamine (32.4 mmol) in 200 g of chloroform). Then, 56.7 g (259.3 mmol) of 2-mesitylenesulfonyl chloride was added, and the reaction mixture was reacted in a two-phase system at 25°C for 24 hours.

[0406] After the reaction, the material was purified in the same manner as in Example 1 to obtain 25.4 g of bis[2-(2-mesitylenesulfonyloxy)ethyl] disulfide (yield 88 mol% / 2-hydroxyethyl disulfide).

[0407] <Bis[2-(2-mesitylenesulfonyloxy)ethyl] disulfide １ H-NMR (400MHz, CDCl ３ )> δ: 2.34 (s, 6H), 2.72 (s, 12H), 2.83-2.86 (t, 4H), 4.19-4.23 (t, 4H), 7.02 (s, 4H)

[0408] [Example 4] <Synthesis of bis[2-(2,4,6-triisopropylbenzenesulfonyloxy)ethyl]disulfide> 20.0 g of a 50% by weight aqueous solution of 2-hydroxyethyl disulfide (64.8 mmol of 2-hydroxyethyl disulfide) was mixed with an aqueous solution of potassium carbonate (53.8 g of potassium carbonate (389.0 mmol) in 200 g of deionized water) and a chloroform solution of triethylamine (3.3 g of triethylamine (32.4 mmol) in 200 g of chloroform). Then, 78.5 g (259.3 mmol) of 2,4,6-triisopropylbenzenesulfonyl chloride was added, and the reaction mixture was reacted in a two-phase system at 25°C for 24 hours.

[0409] After the reaction, the material was purified in the same manner as in Example 1 to obtain 27.6 g of bis[2-(2,4,6-triisopropylbenzenesulfonyloxy)ethyl] disulfide (yield 92 mol% / 2-hydroxyethyl disulfide).

[0410] <Bis[2-(2,4,6-triisopropylbenzenesulfonyloxy)ethyl] disulfide １ H-NMR (400MHz, CDCl ３ )> δ: 1.26-1.33 (m, 18H), 2.83-2.86 (t, 4H), 2.94 (q, 2H), 4.19-4.24 (m, 8H), 7.23 (s, 4H)

[0411] [Comparative Example 1] <Synthesis of bis[2-(methanesulfonyloxy)ethyl]disulfide> 15.0 g (97.2 mmol) of 2-hydroxyethyl disulfide was dissolved in 143 mL of acetonitrile, then 33.3 g (328 mol) of triethylamine was added, and the mixture was cooled to 0°C. 34.5 g (300 mol) of methanesulfonyl chloride was added dropwise to the mixture, and the temperature was raised to 25°C, and the reactants were allowed to react for 3 hours. 39 mL of ethanol was added to the reaction mixture to quench it, and insoluble matter was removed by filtration. 150 mL of dichloromethane and 150 mL of 10% by weight aqueous sodium bicarbonate solution were added to the filtrate and stirred to extract the target product. The mixture was allowed to stand, the lower organic phase was collected, and the collected organic phase was washed four times with 100 mL of water, and then dehydrated with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 25.0 g of bis[2-(methanesulfonyloxy)ethyl] disulfide (yield 81 mol% / 2-hydroxyethyl disulfide).

[0412] <Bis[2-(methanesulfonyloxy)ethyl] disulfide １ H-NMR spectrum (600 MHz, CDCl) ３ )> δ: 2.95-3.20 (m, 10H), 4.45-4.50 (t, 4H)

[0413] [Analysis Method] The purity of the target products in Examples 1-4 and Comparative Example 1 was calculated by thin-layer chromatography (TLC) analysis. For the target products obtained in Examples 1-4, TLC plates were developed with chloroform / methanol = 85 / 15 (volume ratio) and chloroform / methanol = 99 / 1 (volume ratio), and the purity was quantified by color development with iodine. For the target product in Comparative Example 1, TLC plates were developed with chloroform / methanol = 85 / 15 (volume ratio) and chloroform / methanol / 28 wt% ammonia aqueous solution = 80 / 20 / 2 (volume ratio), and the purity was quantified by color development with iodine. The results are shown in Table 1.

[0414]

[0415] As shown in Table 1, the target product (compound (1)) obtained in Examples 1 to 4 has higher purity than the target product obtained in the comparative example, and the method for producing compound (1) of the present invention is useful as a method for producing ionic lipid intermediates.

[0416] The synthesis of ionic lipids using the compounds obtained in Examples 1 to 4 is described below.

[0417] [Example 5-1] Synthesis of compound 1 represented by the following formula

[0418]

[0419] <Synthesis of Bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide> 10.0 g (21.6 mmol) of bis[2-(p-toluenesulfonyloxy)]ethyl]disulfide synthesized by the method described in Example 1 was dissolved in 100 g of acetonitrile, and 16.8 g (129.7 mmol) of 4-piperidineethanol was added. Then, 5.7 g (54.0 mmol) of sodium carbonate was added, and the temperature was raised to 45°C and the reaction was carried out for 2 hours. The reaction solution was diluted with 150 g of chloroform and stirred for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated using an evaporator. An aqueous solution of sodium dihydrogen phosphate was added to the concentrate to adjust the pH to 8.1-8.5, and then the mixture was washed twice with a mixed solvent of 45 g of chloroform and 104 g of toluene. After adding a 1N NaOH aqueous solution and adjusting the pH to 9.1–9.5, the mixture was extracted four times with 266 g of dichloromethane. The resulting organic phase was mixed and then dehydrated with 30 g of sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 6.4 g of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide (yield 79 mol% / bis[2-(p-toluenesulfonyloxy)ethyl] disulfide).

[0420] <Bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide １ H-NMR spectrum (300 MHz, CDCl) ３)> δ: 2.40-2.66 (m, 20H), 2.67-2.72 (m, 4H), 2.74-2.85 (m, 6H), 3.60-3.65 (t, 4H)

[0421] <Synthesis of Compound 1 represented by the above formula> 48.0 g (0.13 mol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide, 112.5 g (0.27 mol) of 4-oleoyloxyphenylacetic acid synthesized by the method described in International Publication No. 2023 / 190164, and 6.2 g (0.05 mol) of DMAP were dissolved in 1680 g of dichloromethane, and then 73.3 g (0.38 mol) of EDC hydrochloride was added and the mixture was reacted at 25°C for 2 hours. The reaction solution was washed with 1200 g of deionized water, and the organic phase was concentrated using an evaporator. The resulting residue was purified by silica gel column chromatography to obtain 117.5 g of Compound 1.

[0422] < Compound 1 １ H-NMR (600MHz, CDCl ３ )> δ: 0.86-0.90 (t, 6H), 1.22-1.42 (m, 46H), 1.54-1.76 (m, 12H), 1.94-2.03 (m, 12H), 2.52-2.56 (m, 4H), 2.62-2.66 ( m, 4H), 2.80-2.89 (m, 8H), 3.59 (s, 4H), 4.11-4.14 (t, 4H), 5.34-5.37 (m, 4H), 7.02-7.05 (m, 4H), 7.26-7.30 (m, 4H)

[0423] [Example 5-2] Compound 1 represented by the above formula was also synthesized by the following method, which is different from that of Example 5-1.

[0424] <Synthesis of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide> 11.8 g (21.6 mmol) of bis[2-(4-tert-butylbenzenesulfonyloxy)]ethyl]disulfide synthesized by the method described in Example 2 was dissolved in 118 g of acetonitrile, and 16.8 g (129.7 mmol) of 4-piperidineethanol was added. Then, 5.7 g (54.0 mmol) of sodium carbonate was added, and the temperature was raised to 45°C and the reaction was carried out for 2 hours.

[0425] After the reaction, the material was purified in the same manner as in the synthesis of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide described in Example 5-1 to obtain 6.5 g of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide (yield 81 mol% / bis[2-(4-tert-butylbenzenesulfonyloxy)ethyl] disulfide).

[0426] <Synthesis of intermediate 1-A shown by the following formula>

[0427]

[0428] 30.0 g (197 mmol) of 4-hydroxyphenylacetic acid and 5.00 g (19.9 mmol) of pyridinium p-toluenesulfonate were dissolved in 120 mL of dichloromethane at 25°C. Then, a dichloromethane solution of DHP (83.0 g (987 mmol) of DHP in 31.1 mL of dichloromethane) was added dropwise at a temperature below 20°C, and the reaction mixture was allowed to react at 25°C for 2 hours. After that, 12.0 g (98.2 mmol) of DMAP was added to the reaction mixture to neutralize it.

[0429] To the obtained mixture, 301 mL of 2-propanol and 160 g of 100 g / L NaOH aqueous solution were added, and the mixture was stirred at 25°C for 1 hour. The mixture was then concentrated using an evaporator, the concentrate was washed with chloroform, and neutralized with 6 M hydrochloric acid. The obtained mixture was extracted using chloroform, and then dehydrated by adding sodium sulfate to the organic phase. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 47.0 g of intermediate 1-A.

[0430] <Synthesis of intermediate 1-B shown by the following formula>

[0431]

[0432] 36.0 g (95.6 mmol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide synthesized by the above method, 49.7 g (210 mmol) of intermediate 1-A, and 4.7 g (38.3 mmol) of DMAP were dissolved in 240 mL of chloroform at 25°C. Then, 55.1 g (287 mmol) of EDC hydrochloride was added and the mixture was reacted at 25°C for 2 hours. The reaction solution was then washed with 5 wt% aqueous sodium dihydrogen phosphate, 9 wt% aqueous sodium bicarbonate, and 20 wt% saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 77.9 g of intermediate 1-B.

[0433] <Synthesis of intermediate 1 shown by the following formula>

[0434]

[0435] 77.7 g (96 mmol) of intermediate 1-B was dissolved in 325 mL of THF at 25°C, and 319 mL of 2-propanol and 38.2 g (201 mmol) of p-toluenesulfonic acid monohydrate were added and the mixture was reacted at 25°C for 1 hour. Then, 25.0 g (205 mmol) of DMAP was added to the reaction mixture to neutralize it. After removing the salt precipitated by neutralization by filtration, the filtrate was concentrated using an evaporator. The obtained residue was dissolved in 627 mL of chloroform, washed with 0.5 M phosphate buffer (pH = 6.5) and 0.5 M glycine buffer (pH = 9.5), and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, crystallization was performed by adding 1.56 L of toluene. The obtained crude product was washed with hexane and then vacuum dried to obtain 40.3 g of intermediate 1.

[0436] <Synthesis of Compound 1 represented by the above formula> 11.0 g (17 mmol) of intermediate 1, 9.64 g (34 mmol) of oleic acid, and 834 mg (6.8 mmol) of DMAP were dissolved in 165 g of chloroform at 25°C, and then 9.81 g (51 mmol) of EDC hydrochloride was added and the mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was purified in the same manner as the synthesis of Compound 1 described in Example 5-1 to obtain 11.5 g of Compound 1.

[0437] [Example 6] Synthesis of compound 2 represented by the following formula

[0438]

[0439] <Synthesis of Bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}Disulfide> 11.2 g (21.6 mmol) of bis[2-(2-mesitylenesulfonyloxy)ethyl]disulfide synthesized by the method described in Example 3 was dissolved in 112 g of acetonitrile, and 16.8 g (129.7 mmol) of 4-piperidineethanol was added. Then, 5.7 g (54.0 mmol) of sodium carbonate was added, and the temperature was raised to 45°C and the reaction was carried out for 2 hours. After the reaction, the mixture was purified by the method described in Example 5-1 to obtain 6.0 g of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide (yield 75 mol% / bis[2-(2-mesitylenesulfonyloxy)ethyl]disulfide).

[0440] <Synthesis of Compound 2 represented by the above formula> Using 3.0 g (7.9 mmol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide obtained by the above method and 8.46 g (15.9 mmol) of D-α-tocopherol succinate, 7.3 g of Compound 2 was synthesized in the same manner as the synthesis of Compound 1 described in Example 5-1.

[0441] < Compound 2 １ H-NMR (400MHz, CDCl ３ )> δ: 0.83-0.87 (m, 24H), 1.04-1.16 (m, 16H), 1.20-1.42 (m, 28H), 1.49-1.61 (m, 14H), 1.68 (d, 4H), 1.77 (t, 4H), 1. 93-2.01 (m, 16H), 2.08 (s, 6H), 2.56-2.65 (m, 8H), 2.75 (t, 4H), 2.80-2.84 (m, 4H), 2.87-2.94 (m, 8H), 4.15 (t, 4H)

[0442] [Example 7] Synthesis of compound 3 represented by the following formula

[0443]

[0444] <Synthesis of Bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide> 14.9 g (21.6 mmol) of bis[2-(2,4,6-triisopropylbenzenesulfonyloxy)ethyl]disulfide synthesized by the method described in Example 4 was dissolved in 149 g of acetonitrile, and 16.8 g (129.7 mmol) of 4-piperidineethanol was added. Then, 5.7 g (54.0 mmol) of sodium carbonate was added, and the temperature was raised to 45°C and the reaction was carried out for 2 hours. After the reaction, the mixture was purified by the method described in Example 5-1 to obtain 6.7 g of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide (yield 83 mol% / bis[2-(2,4,6-triisopropylbenzenesulfonyloxy)ethyl]disulfide).

[0445] <Synthesis of Intermediate 1 represented by the above formula> 18.5 g (49.1 mmol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl} disulfide synthesized by the above method, 27.9 g (118 mmol) of intermediate 1-A synthesized by the method of Example 5-2, and 2.4 g (19.6 mmol) of DMAP were dissolved in 185 g of chloroform at 25°C, and then 28.3 g (147 mmol) of EDC hydrochloride was added and the mixture was reacted at 25°C for 2 hours. After that, the reaction solution was washed twice with 185 g of deionized water, and then 55.5 g of 2-propanol and 24.3 g of p-toluenesulfonic acid monohydrate were added and the mixture was stirred for 2 hours. After stirring, the solution was washed three times with 185 g of 8 wt% aqueous sodium bicarbonate solution, and the resulting organic phase was concentrated in an evaporator. 185 g of acetonitrile was added to the concentrate and stirred, and the crude crystals were recovered by filtration. 102 g of chloroform and 26 g of 2-propanol were added to the crude crystals, dissolved at 40°C, and then cooled to 25°C for crystallization. After crystallization was performed a total of three times, the obtained crystals were vacuum-dried to obtain 23.1 g of intermediate 1.

[0446] <Synthesis of intermediate 2 shown by the following formula>

[0447]

[0448] 5.11 g (18.1 mmol) of oleic acid, 16.6 g (25.8 mmol) of intermediate 1 synthesized by the above method, and 630 mg (5.16 mmol) of DMAP were dissolved in 166 mL of chloroform at 25°C. 5.94 g (31.0 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 2 hours. The reaction solution was then washed with 5 wt% aqueous sodium hydrogen phosphate, 0.5 M phosphate buffer (pH = 2.0), and 20 wt% saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator. The resulting residue was purified by silica gel column chromatography (chloroform / ethanol = 88 / 12 (volume ratio)) to obtain 8.21 g of intermediate 2.

[0449] <Synthesis of intermediate 3-1 shown by the following formula>

[0450]

[0451] 5.00 g (16.0 mmol) of methyl ricinolate, 2.54 g (17.6 mmol) of octanoic acid, and 391 mg (3.20 mmol) of DMAP were dissolved in 50.0 g of chloroform at 25°C. 4.60 g (24.0 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. The reaction solution was then washed with 0.5 M phosphate buffer (pH = 4.0), 7% by weight sodium bicarbonate solution, and 20% by weight saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 6.78 g of intermediate 3-1.

[0452] <Synthesis of intermediate 3-2 shown by the following formula>

[0453]

[0454] Intermediate 3-1 was dissolved in tert-butanol at 25°C to a concentration of 0.3 M (6.40 g, 14.6 mmol) at 25°C. 8.17 g of 2 M aqueous NaOH solution was added to the resulting mixture and reacted at 25°C for 8 hours. Then, 1 M hydrochloric acid was added, and the resulting mixture was extracted with hexane. The organic phase was washed with 20% by weight saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator. The resulting residue was purified by silica gel column chromatography to obtain 5.93 g of intermediate 3-2.

[0455] <Synthesis of Compound 3 represented by the above formula> Using 3.00 g (3.30 mmol) of intermediate 2 and 1.47 g (3.46 mmol) of intermediate 3-2, 2.82 g of compound 3 was synthesized in the same manner as the synthesis of compound 1 described in Example 5-2.

[0456] < Compound 3 １ H-NMR (600MHz, CDCl ３ )> δ: 0.86-0.90 (m, 9H), 1.22-1.42 (m, 50H), 1.54-1.76 (m, 16H), 1.91-1.98 (m , 4H), 2.00-2.06 (m, 6H), 2.23-2.33 (m, 4H), 2.52-2.56 (m, 4H), 2.61-2.67 (m , 4H), 2.79-2.92 (m, 8H), 3.59 (s, 4H), 4.11-4.14 (t, 4H), 4.85-4.90 (m, 1H) , 5.31-5.40 (m, 3H), 5.44-5.49 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.30 (m, 4H)

[0457] [Example 8] Synthesis of compound 4 represented by the following formula

[0458]

[0459] <Synthesis of intermediate 4-1 shown by the following formula>

[0460]

[0461] 5.03 g (16.0 mmol) of methyl ricinolate, 2.26 g (17.6 mmol) of cyclohexanecarboxylic acid, and 389 mg (3.20 mmol) of DMAP were dissolved in 50.3 g of chloroform at 25°C. 4.60 g (24.0 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. The reaction solution was then washed with 0.5 M phosphate buffer (pH 4.0), 7% by weight sodium bicarbonate solution, and 20% by weight saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 6.31 g of intermediate 4-1.

[0462] <Synthesis of intermediate 4-2 shown by the following formula>

[0463]

[0464] 6.31 g (14.9 mmol) of intermediate 4-1 was dissolved in tert-butanol to a concentration of 0.3 M at 25°C. 8.35 g of 2 M NaOH aqueous solution was added to the resulting mixture and the mixture was reacted at 25°C for 8 hours. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 3-2 in Example 7 to obtain 4.95 g of intermediate 4-2.

[0465] <Synthesis of intermediate 4 shown by the following formula>

[0466]

[0467] Using 5.0 g (7.75 mmol) of intermediate 1 and 1.58 g (3.87 mmol) of intermediate 4-2, 4.0 g of intermediate 4 was synthesized in the same manner as the synthesis of intermediate 2 described in Example 7.

[0468] <Synthesis of Compound 4 represented by the above formula> Using 2.00 g (1.93 mmol) of intermediate 4 and 0.99 g (2.03 mmol) of cholesterol hydrogen succinate, 1.89 g of compound 4 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0469] < Compound 4 １ H-NMR (600MHz, CDCl ３)> δ: 0.64-0.78 (m, 3H), 0.83-0.88 (m, 9H), 0.89-1.02 (m, 7H), 1.03-1.17 (m, 3H), 1.19-1.46 (m, 22H), 1.47-1.6 7 (m, 38H), 1.69-1.77 (m, 4H), 1.78-1.91 (m, 4H), 192-2.08 (m, 6H), 2.22-2.35 (m, 4H), 2.51-2.56 (m, 2H), 2.6 1-2.66 (m, 4H), 2.69-2.74 (m, 2H), 2.78-2.84 (m, 3H), 2.85-2.91 (m, 6H), 3.59 (s, 4H), 4.09-4.14 (t, 4H), 4.6 2-4.69 (m, 1H), 4.84-4.90 (m, 1H), 5.29-5.38 (m, 2H), 5.43-5.50 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.29 (m, 4H)

[0470] [Example 9] Synthesis of compound 5 represented by the following formula

[0471]

[0472] <Synthesis of intermediate 5-1 shown by the following formula>

[0473]

[0474] 25.0 g (189 mmol) of (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol and 19.3 g (284 mmol) of imidazole were dissolved in 251 g of dimethylformamide at 25°C. 57.3 g (208 mmol) of TBDPS-Cl was added to the resulting mixture and reacted at 25°C for 1 hour. Then, chloroform was added to the reaction solution, and after washing with 5% by weight aqueous solution of sodium hydrogen phosphate and deionized water, sodium sulfate was added to dehydrate the mixture. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 56.0 g of intermediate 5-1.

[0475] <Synthesis of intermediate 5-2 shown by the following formula>

[0476]

[0477] Intermediate 5-1 was prepared by dissolving 55.9 g (151 mmol) of intermediate 5-1 in 503 g of 0.5 M phosphate buffer (pH 1.0) at 25°C in 530 g of THF and reacting at 50°C for 12 hours. After the reaction, 1.0 M NaOH aqueous solution was added to adjust the pH to 7.0. Chloroform was added to the resulting mixture, and after washing with 20% by weight saline solution, sodium sulfate was added to dehydrate it. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 44.9 g of intermediate 5-2.

[0478] <Synthesis of intermediate 5-3 shown by the following formula>

[0479]

[0480] Intermediate 5-2 was prepared by dissolving 6.90 g (20.9 mmol) of intermediate 5-2, 6.84 g (46.0 mmol) of heptanoic acid, and 0.511 g (4.18 mmol) of DMAP in 69.5 g of chloroform at 25°C. 12.0 g (62.7 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. The reaction solution was then washed with 0.5 M phosphate buffer (pH 4.0), 7% by weight sodium bicarbonate solution, and 20% by weight saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 9.03 g of intermediate 5-3.

[0481] <Synthesis of intermediate 5-4 shown by the following formula>

[0482]

[0483] Intermediate 5-3 was dissolved in 27.2 g of THF at 25°C with 9.41 g (17.9 mmol) of intermediate 5-3 and 3.92 g (65.3 mmol) of acetic acid. 59.9 g (65.2 mmol) of a 1 M TBAF solution in THF was added to the resulting mixture and reacted at 25°C for 18 hours. Subsequently, 94.3 g of ethyl acetate was added to the reaction solution, and after washing with 0.5 M phosphate buffer (pH 4.0) and 20% by weight saline solution, sodium sulfate was added to dehydrate the mixture. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 4.90 g of intermediate 5-4.

[0484] <Synthesis of intermediate 5-5 shown by the following formula>

[0485]

[0486] Intermediate 5-4 (4.90 g, 15.4 mmol), glutaric anhydride (3.73 g, 32.7 mmol), triethylamine (4.95 g, 48.9 mmol), and DMAP (0.398 g, 3.26 mmol) were dissolved in 51.6 g of chloroform and reacted at 25°C for 1 hour. The reaction solution was then washed with 0.5 M phosphate buffer (pH = 4.0), 7% sodium bicarbonate solution, and 20% saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 3.16 g of intermediate 5-5.

[0487] <Synthesis of intermediate 5 shown by the following formula>

[0488]

[0489] Using 4.60 g (7.1 mmol) of intermediate 1 and 1.53 g (3.56 mmol) of intermediate 5-5, 5.65 g of intermediate 5 was synthesized in the same manner as the synthesis of intermediate 2 described in Example 7.

[0490] <Synthesis of tocopherol and glutaric acid esters shown in the following formula>

[0491]

[0492] 5.00 g (11.6 mmol) of tocopherol, 2.65 g (23.2 mmol) of glutaric anhydride, 425 mg (3.48 mmol) of DMAP, and 3.52 g (34.8 mmol) of triethylamine were dissolved in 50.0 g of chloroform and reacted at 25°C for 12 hours. Subsequently, 6.19 g of tocopherol and glutaric acid ester was obtained in the same manner as in the synthesis of intermediates 4-5 described in Example 4.

[0493] <Synthesis of Compound 5 represented by the above formula> Using 2.30 g (2.18 mmol) of intermediate 5 and 1.21 g (2.28 mmol) of the ester of tocopherol and glutaric acid, 2.22 g of compound 5 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0494] < Compound 5 １H-NMR (600MHz, CDCl ３ )> δ: 0.83-0.90 (m, 18H), 1.02-1.44 (m, 36H), 1.48-1.68 (m, 16H), 1.71-1.83 (m, 2H), 1.91-1.98 (m, 7H), 1. 99-2.03 (m, 3H), 2.04-2.10 (m, 5H), 2.18-2.24 (m, 2H), 2.29-2.34 (m, 4H), 2.45-2.50 (m, 2H), 2.57-2.60 ( m, 2H), 2.61-2.66 (m, 6H), 2.71-2.78 (m, 4H), 2.79-2.84 (m, 4H), 2.85-2.90 (m, 4H), 3.59 (s, 4H), 3.69-2. 76 (m, 2H), 4.10-4.18 (m, 6H), 4.29-4.36 (m, 2H), 5.24-5.30 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.29 (m, 4H)

[0495] [Example 10] Synthesis of compound 6 represented by the following formula

[0496]

[0497] <Synthesis of intermediate 6-1 shown by the following formula>

[0498]

[0499] 1.00 g (3.20 mmol) of methyl ricinoleate and 436 mg (6.40 mmol) of imidazole were dissolved in 10.5 mL of dimethylformamide at 25°C. 772 mg (5.12 mmol) of TBS-Cl was added to the resulting mixture and the mixture was reacted at 25°C for 7 hours. Chloroform was then added to the reaction solution, and the mixture was washed with 5% by weight aqueous solution of sodium hydrogen phosphate and deionized water, respectively. Sodium sulfate was then added to dehydrate the mixture. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 1.00 g of intermediate 6-1.

[0500] <Synthesis of intermediate 6 shown by the following formula>

[0501]

[0502] Intermediate 5-1 (1.00 g, 2.34 mmol) was dissolved in 4.95 mL of tert-butanol at 25°C. 1.83 g of 2 M NaOH aqueous solution was added to the resulting mixture and the mixture was reacted at 25°C for 8 hours. After the reaction, the mixture was purified in the same manner as the synthesis of intermediate 3-2 described in Example 7 to obtain 774 mg of intermediate 6.

[0503] <Synthesis of Compound 6 represented by the above formula> Using 1.00 g (1.10 mmol) of intermediate 2 and 477 mg (1.15 mmol) of intermediate 6, 929 mg of compound 6 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0504] < Compound 6 １ H-NMR (600MHz, DMSO-d ６ )> δ: 0.21 (s, 6H), 0.86-0.89 (m, 6H), 0.98 (s, 9H), 1.22-1.42 (m, 44H), 1.54- 1.76 (m, 12H), 1.91-1.98 (m, 6H), 1.99-2.16 (m, 6H), 2.52-2.56 (m, 4H), 2. 62-2.66 (m, 4H), 2.78-2.92 (m, 8H), 3.51-3.59 (m, 5H), 4.11-4.13 (t, 4H), 5.30-5.38 (m, 3H), 5.50-5.58 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.29 (m, 4H)

[0505] [Example 11] Synthesis of compound 7 represented by the following formula

[0506]

[0507] Compound 6 was dissolved in 6.40 mL of isopropanol at 25°C. 87.5 mg (0.460 mmol) of p-toluenesulfonic acid monohydrate was added to the resulting mixture and the mixture was reacted at 25°C for 7 hours. Subsequently, 6.40 mL of chloroform was added to the reaction solution, and the mixture was washed with 5% by weight aqueous sodium bicarbonate and 20% by weight saline solution. Sodium sulfate was then added to dehydrate the mixture. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator. The resulting residue was purified by silica gel column chromatography to obtain 204 mg of compound 7.

[0508] < Compound 7 １ H-NMR (600MHz, DMSO-d ６ )> δ: 0.86-0.89 (m, 6H), 1.22-1.42 (m, 44H), 1.54-1.76 (m, 12H), 1.91-1.98 (m, 6H), 1.99-2.16 (m, 6H), 2.52-2.56 (m, 4H), 2.62-2.66 (m, 4) H), 2.78-2.92 (m, 8H), 3.51-3.59 (m, 5H), 4.11-4.13 (t, 4H), 5.30-5.38 (m, 3H), 5.50-5.58 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.29 (m, 4H)

[0509] [Example 12] Synthesis of compound 8 represented by the following formula

[0510]

[0511] <Synthesis of intermediate 7-1 shown by the following formula>

[0512]

[0513] 1.00 g (3.90 mmol) of 9-heptadecanol and 3.35 g (33.1 mmol) of triethylamine were dissolved in 7.50 mL of dichloromethane at 25°C. 7.99 g (31.1 mmol) of DSC was added to the resulting mixture and the mixture was reacted at 25°C for 30 hours. After filtering the reaction solution, 1.20 g (7.80 mmol) of 4-methyl aminobutyrate hydrochloride was added and the mixture was reacted at 25°C for 4 hours. The reaction solution was then washed with 5% by weight sodium dihydrogen phosphate aqueous solution, 7% by weight sodium bicarbonate aqueous solution, and 20% by weight saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 977 mg of intermediate 7-1.

[0514] <Synthesis of intermediate 7 shown by the following formula>

[0515]

[0516] Intermediate 7-1 was dissolved in 6.52 mL of tert-butanol at 25°C. 1.35 g of 2 M NaOH aqueous solution was added to the resulting mixture and the mixture was reacted at 25°C for 2 hours. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 3-2 in Example 7 to obtain 634 mg of intermediate 7.

[0517] <Synthesis of Compound 8 represented by the above formula> Using 800 mg (0.88 mmol) of intermediate 2 and 356 mg (0.92 mmol) of intermediate 7, 764 mg of compound 8 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0518] < Compound 8 １ H-NMR (600MHz, DMSO-d ６ )> δ: 0.82-0.94 (m, 9H), 1.16-1.71 (m, 64H), 1.98-2.08 (m, 2H), 2.11-2.22 (m, 4H), 2.32-2.68 (m, 20H), 3.18 (t, 2H), 3.71 (s, 4H), 4.13 (t, 4H), 4.38-4.53 (m, 1H), 5.24-5.38 (m, 2H), 6.76 (brs, 1H), 7.13-7.22 (m, 8H)

[0519] [Example 13] Synthesis of compound 9 represented by the following formula

[0520]

[0521] <Synthesis of intermediate 8-1 shown by the following formula>

[0522]

[0523] 1.48 g (7.68 mmol) of citric acid, 3.76 g (50.7 mmol) of 1-butanol, and 938 mg (7.68 mmol) of DMAP were dissolved in 23.7 g of dichloromethane at 25°C. 9.72 g (50.7 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. After the reaction, the mixture was purified in the same manner as the synthesis of intermediate 2 described in Example 7 to obtain 2.78 g of intermediate 8-1.

[0524] <Synthesis of intermediate 8 shown by the following formula>

[0525]

[0526] Intermediate 8-1 (2.78 g, 7.42 mmol), glutaric anhydride (1.69 g, 14.8 mmol), DMAP (906 mg, 7.42 mmol), and pyridine (2.35 g, 29.7 mmol) were dissolved in 41.7 g of chloroform at 25°C and reacted for 9 hours. Then, 1.54 g of intermediate 8 was obtained in the same manner as the synthesis of intermediates 4-5 described in Example 4.

[0527] <Synthesis of Compound 9 represented by the above formula> Using 2.30 g (2.53 mmol) of intermediate 2 and 1.30 g (2.67 mmol) of intermediate 8, 2.03 g of compound 9 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0528] < Compound 9 １ H-NMR (600MHz, DMSO-d ６ )> δ: 0.86-0.89 (m, 12H), 1.22-1.76 (m, 48H), 1.91-1.98 (m, 4H), 1.99-2.16 (m, 6H), 2.28-2.38 (m, 4H), 2.41 (s, 6H), 2.52-2.56 (t, 2H) ), 2.62-2.66 (m, 4H), 2.78-2.92 (m, 8H), 3.59 (s, 4H), 4.11-4.15 (t, 10H), 5.30-5.38 (m, 2H), 7.02-7.04 (m, 4H), 7.26-7.29 (m, 4H)

[0529] [Example 14] Synthesis of compound 10 represented by the following formula

[0530]

[0531] <Synthesis of intermediate 9 shown by the following formula>

[0532]

[0533] 2.00 g (10.6 mmol) of azelaic acid, 756 mg (5.31 mmol) of 1-nonane-3-ol, and 649 mg (5.31 mmol) of DMAP were dissolved in 50.0 g of chloroform at 25°C. 1.22 g (6.36 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 2 described in Example 7 to obtain 2.63 g of intermediate 9.

[0534] <Synthesis of Compound 10 represented by the above formula> Using 3.34 g (3.67 mmol) of intermediate 2 and 1.21 g (3.86 mmol) of intermediate 9, 2.69 g of compound 10 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0535] < Compound 10 １ H-NMR (600MHz, CDCl ３ )> δ: 0.86-0.89 (m, 6H), 1.22-1.42 (m, 32H), 1.54-1.76 (m, 16H), 1.91-1. 98 (m, 4H), 2.00-2.06 (m, 8H), 2.23-2.33 (m, 2H), 2.52-2.67 (m, 16H), 2. 79-2.92 (m, 4H), 3.59 (s, 4H), 4.11-4.14 (t, 4H), 5.31-5.39 (m, 4H), 5.4 4-5.49 (m, 1H), 5.89-5.91 (m, 1H), 7.02-7.04 (m, 4H), 7.26-7.30 (m, 4H)

[0536] [Example 15] Synthesis of compound 11 represented by the following formula

[0537]

[0538] <Synthesis of intermediate 10-1 shown by the following formula>

[0539]

[0540] 4.99 g (15.1 mmol) of methyl 9,10-dihydroxystearate, 2.35 g (31.8 mmol) of propionic acid, and 745 mg (6.10 mmol) of DMAP were dissolved in 56.6 g of chloroform at 25°C. 8.70 g (45.4 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. The reaction solution was then washed with a 5 wt% aqueous sodium hydrogen phosphate solution and a 20 wt% saline solution, and then dehydrated with sodium sulfate. After removing the sodium sulfate by filtration, the filtrate was concentrated using an evaporator to obtain 6.36 g of intermediate 10-1.

[0541] <Synthesis of intermediate 10 shown by the following formula>

[0542]

[0543] 5.00 g (11.3 mmol) of intermediate 10-1 was dissolved in 29.6 g of tert-butanol at 25°C. 6.21 g of 2 M NaOH aqueous solution was added to the resulting mixture and the mixture was reacted at 25°C for 8 hours. After the reaction, 3.87 g of intermediate 10 was obtained in the same manner as intermediate 3-2 described in Example 7.

[0544] <Synthesis of Compound 11 represented by the above formula> Using 4.50 g (4.95 mmol) of intermediate 2 and 2.38 g (5.19 mmol) of intermediate 10, 4.80 g of compound 11 was synthesized in the same manner as the synthesis of compound 3 described in Example 7.

[0545] < Compound 11 １ H-NMR (600MHz, DMSO-d ６ )> δ: 0.84-0.90 (m, 6H), 1.16-1.76 (m, 68H), 2.08-2.20 (m, 4H), 2.13-2.73 (m, 24H), 3.71 (s, 4H), 4.13 (t, 4H), 5.01-5.12 (m, 2H), 5.27-5.43 (m, 2H), 7.13-7.22 (m, 8H)

[0546] [Example 16] Synthesis of compound 12 represented by the following formula

[0547]

[0548] Using 6.25 g (9.69 mmol) of intermediate 1 and 8.07 g (2.04 mmol) of intermediate 3-2, 7.07 g of compound 12 was synthesized in the same manner as the synthesis of compound 1 described in Example 5-1.

[0549] < Compound 12 １ H-NMR (600MHz, CDCl ３ )> δ: 0.86-0.89 (m, 12H), 1.22-1.42 (m, 38H), 1.54-1.76 (m, 16H), 1.91-1.98 ( m, 4H), 2.00-2.06 (m, 8H), 2.23-2.33 (m, 8H), 2.52-2.56 (m, 4H), 2.61-2.67 ( m, 4H), 2.79-2.92 (m, 8H), 3.59 (s, 4H), 4.11-4.14 (t, 4H), 4.85-4.90 (m, 2H) , 5.31-5.39 (m, 2H), 5.44-5.49 (m, 2H), 7.02-7.04 (m, 4H), 7.26-7.30 (m, 4H)

[0550] [Example 17] Synthesis of compound 13 represented by the following formula

[0551]

[0552] <Synthesis of intermediate 12-1 shown by the following formula>

[0553]

[0554] 4.00 g (12.8 mmol) of methyl ricinolate, 2.77 g (13.4 mmol) of lipoic acid, and 313 mg (2.56 mmol) of DMAP were dissolved in 40.0 g of chloroform at 25°C. 3.68 g (19.1 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 2 described in Example 7 to obtain 6.34 g of intermediate 12-1.

[0555] <Synthesis of intermediate 12 shown by the following formula>

[0556]

[0557] Intermediate 12-1 was dissolved in 6.34 g (12.7 mmol) of tert-butanol at 25°C to a concentration of 0.3 M. 7.09 g of 2 M NaOH aqueous solution was added to the resulting mixture and the mixture was reacted at 25°C for 8 hours. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 3-2 in Example 7 to obtain 5.52 g of intermediate 12.

[0558] <Synthesis of Compound 13 represented by the above formula> Using 500 mg (0.78 mmol) of intermediate 1 and 793 mg (1.63 mmol) of intermediate 12, 773 mg of compound 13 was synthesized in the same manner as the synthesis of compound 1 described in Example 5-2.

[0559] < Compound 13 １ H-NMR (600MHz, CDCl ３ )> δ: 0.86-0.89 (m, 6H), 1.22-1.42 (m, 50H), 1.54-1.76 (m, 16H), 1.91-1.98 (m , 4H), 2.00-2.06 (m, 8H), 2.23-2.33 (m, 12H), 2.52-2.56 (m, 6H), 2.61-2.67 ( m, 4H), 2.79-2.92 (m, 8H), 3.59 (s, 4H), 4.11-4.14 (t, 4H), 4.85-4.90 (m, 2H) , 5.31-5.39 (m, 2H), 5.44-5.49 (m, 2H), 7.02-7.04 (m, 4H), 7.26-7.30 (m, 4H)

[0560] [Example 18] Synthesis of compound 14 represented by the following formula

[0561]

[0562] <Synthesis of intermediate 13 shown by the following formula>

[0563]

[0564] 7.34 g (39 mmol) of azelaic acid, 5.00 g (19 mmol) of 9-heptadecanol, and 2.37 g (19 mmol) of DMAP were dissolved in 150 g of chloroform at 25°C. 3.74 g (19 mmol) of EDC hydrochloride was added to the resulting mixture and the mixture was reacted at 25°C for 1 hour. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediate 2 described in Example 7 to obtain 2.63 g of intermediate 13.

[0565] <Synthesis of Compound 14 represented by the above formula> Using 1.60 g (1.76 mmol) of intermediate 2 and 1.58 g (3.69 mmol) of intermediate 13, 1.67 g of compound 14 was synthesized in the same manner as the synthesis of compound 3 described in Example 6.

[0566] < Compound 14 １ H-NMR (300MHz, CDCl ３ )> δ: 0.86 (t, 9H), 1.23-1.48 (m, 54H), 1.46-1.78 (m, 22H), 1.87-2.05 (m, 8H), 2.28 (t, 2H), 2.53 (t, 4H), 2.6 2 (m, 4H), 2.70-2.91 (m, 8H), 3.58 (s, 4H), 4.11 (t, 4H), 4.86 (m, 1H), 5.34 (m, 2H), 7.01 (d, 4H), 7.25 (d, 4H)

[0567] [Example 19] Synthesis of compound 15 represented by the following formula

[0568]

[0569] <Synthesis of intermediate 14 shown by the following formula>

[0570]

[0571] 10.0 g (7.42 mmol) of 2-hexyl-1-decanol, 8.3 g (14.8 mmol) of succinic anhydride, and 5.0 g (7.42 mmol) of DMAP were dissolved in 150 g of chloroform at 25°C and reacted for 2 hours. After the reaction, the mixture was purified in the same manner as in the synthesis of intermediates 4-5 described in Example 9 to obtain 9.3 g of intermediate 14.

[0572] <Synthesis of Compound 15 represented by the above formula> Using 2.29 g (6.69 mmol) of intermediate 14 and 1.20 g (3.19 mmol) of bis{2-[4-(2-hydroxyethyl)piperidyl]ethyl}disulfide synthesized by the method described in Example 5-1, 2.12 g of compound 15 was synthesized in the same manner as the synthesis of compound 1 described in Example 5-1.

[0573] < Compound 15 １ H-NMR (500MHz, CDCl３ )> δ: 0.91 (t, 12H), 1.1-1.5 (m, 54H), 1.5-1.8 (m, 10H), 1.9-2.2 (q, 4H), 3.2-3.5 (m, 20H), 4.01 (t, 4H), 4.15 (t, 4H)

[0574] [Example 20] Synthesis of compound 16 represented by the following formula

[0575]

[0576] Using 5.77 g (16.3 mmol) of 5,5-bis(((Z)-octa-5-en-1-yl)oxy)pentanoic acid synthesized by the method described in International Publication No. 2023 / 121964 and 5.00 g (7.75 mmol) of intermediate 1, 7.15 g of compound 16 was synthesized in the same manner as the synthesis of compound 1 described in Example 5-2.

[0577] < Compound 16 １ H-NMR (400MHz, CDCl ３ )> δ: 0.94 (t, 12H), 1.16-1.35 (m, 10H), 1.35-1.48 (m, 9H), 1.63 (s, 23H), 1.87-2.13 (m, 12H), 2.55-2.74 (m, 7H), 2.75-3. 01 (m, 8H), 3.38-3.51 (m, 4H), 3.52-3.73 (m, 9H), 4.11 (t, 4H), 4.55 (t, 2H), 5.25-5.42 (m, 8H), 7.02 (d, 4H), 7.27 (d, 4H)

[0578] According to the manufacturing method of the present invention, a compound (1) useful as a synthesis intermediate for ionic lipids (7a) and ionic lipids (7b) can be obtained in high purity.

[0579] This application is based on Japanese Patent Application No. 2024-168669, which is entirely contained herein.

Claims

1. Method for producing the compound represented by formula (1) below, including step 1a below: Step 1a: In a two-phase system containing an organic base, an inorganic base, water, and a water-insoluble organic solvent, a compound represented by formula (3) below and a compound represented by formula (4) below are reacted to obtain the compound represented by formula (1) below. (In formula (1), R １ａ and R １ｂ Each of these independently represents an alkylene group having 1 to 6 carbon atoms, and both A's are in formula (2) (In equation (2), * represents the bond position, and R ２ ~R ６ Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano group, a nitro group, a trifluoromethyl group, or a trifluoromethoxy group. (In formula (3), R １ａ and R １ｂ As stated above.) (In formula (4), R ２ ~R ６ This is as stated above.

2. The manufacturing method according to claim 1, wherein the organic base is at least one selected from the group consisting of trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dimethylbenzylamine, N-butyldimethylamine, pyridine, and 4-dimethylaminopyridine.

3. The manufacturing method according to claim 1 or 2, wherein the inorganic base is at least one selected from the group consisting of sodium carbonate and potassium carbonate.

4. The method for producing a product according to claim 1 or 2, wherein the non-water-soluble organic solvent is at least one selected from the group consisting of chloroform and dichloromethane.

5. R １ａ and R １ｂ The production method according to claim 1 or 2, wherein R and R are each independently an alkylene group having 1 to 3 carbon atoms.

6. R ２ ~R ６ The manufacturing method according to claim 1 or 2, wherein each is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

7. Compounds represented by the following formula (1): (In formula (1), R １ａ and R １ｂ Each of these independently represents an alkylene group having 1 to 6 carbon atoms, and both A's are from formula (2): (In equation (2), * represents the bond position, and R ２ ~R ６ Each of these independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano group, a nitro group, a trifluoromethyl group, or a trifluoromethoxy group.

8. R １ａ and R １ｂ However, each is independently an alkylene group having 1 to 3 carbon atoms, as described in claim 7.

9. R ２ ~R ６ The compound according to claim 7 or 8, wherein each is independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

10. A method for producing a compound represented by formula (5) below, comprising the following steps 2a and 2b: Step 2a, which involves obtaining a compound represented by formula (1) by the production method described in claim 1 or 2; and Step 2b, which involves reacting the compound represented by formula (1), the compound represented by formula (6a), and the compound represented by formula (6b) below to obtain a compound represented by formula (5) below. (In formula (5), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, and R ７ａ and R ７ｂ Each of these independently represents either an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms. (In equations (6a) and (6b), X ａ , X ｂ , R ７ａ , and R ７ｂ As stated above, the hydrogen atom at the far right of equation (6a) is X ａ It is bonded to the nitrogen atom inside, and the hydrogen atom at the far right of formula (6b) is X ｂ It is bonded to the nitrogen atom inside.

11. A method for producing an ionic lipid represented by the following formula (7a), comprising the following steps 3a and 3b: Step 3a, which involves obtaining a compound represented by formula (5) by the production method described in claim 10; and Step 3b, which involves reacting the compound represented by formula (5), the compound represented by the following formula (19a), and the compound represented by the following formula (19b) to obtain an ionic lipid represented by the following formula (7a). (In formula (7a), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each independently represents an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms, and each independently represents 0 or 1, Z ａ and Z ｂ Each independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, having at least one aromatic ring, and possibly having a heteroatom, and R ８ａ and R ８ｂ Each of these independently comprises: (i) a monovalent group having 10 to 50 carbon atoms having one carbonyl group and at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (ii) a monovalent group having 10 to 50 carbon atoms having at least two carbonyl groups (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (iii) formula (8): *-R ９ -X １ -R １０ (8) (In equation (8), * indicates the bonding position, R ９ X represents an alkylene group with 1 to 10 carbon atoms. １ R represents a carbamate bond, carbonate bond, or amide bond, and １０ represents an alkyl group having 1 to 25 carbon atoms, and R １０ (iv) Formula (9): *-R １１ -CO-O-R １２ (9) In equation (9), * represents the bonding position, R １１ R represents an alkylene group having 1 to 10 carbon atoms, and １２ represents an alkyl group having 1 to 25 carbon atoms that is substituted with at least one halogen atom. ) A monovalent group represented by formula (v) (10): (In equation (10), * represents the bond position, R １３ and R １４ Each of these independently represents an alkylene group with 1 to 10 carbon atoms, an alkenediyl group with 2 to 10 carbon atoms, or an alkynediyl group with 2 to 10 carbon atoms, R １５ ~R １７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (vi) Formula (11): (In equation (11), * represents the bonding position, X ２ is a nitrogen atom or formula (12): (In equation (12), * represents R ２１ This represents the bond position with, and ** is R ２２ or R ２３ This represents the bonding position with ( ). ) represents the trivalent group indicated by X ２ When R is a nitrogen atom, ２１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ２１ may be substituted with a substituent selected from the group consisting of a halogen atom and a hydroxy group, and X ２ When is a trivalent group represented by the formula (12), R ２１ represents an alkylene group having 1 to 10 carbon atoms, and R ２１ may be substituted with a substituent selected from the group consisting of a halogen atom and a hydroxy group, and X ２ When is a nitrogen atom, R ２２ and R ２３ each independently represent an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and R ２２ and R ２３ may each independently be substituted with a substituent selected from the group consisting of a halogen atom and a hydroxy group, and, X ２ When is a trivalent group represented by the formula (12), R ２２ and R ２３ each independently represent an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ may each independently be substituted with a substituent selected from the group consisting of a halogen atom and a hydroxy group. ), a monovalent group represented by (vii) formula (13): (In formula (13), * represents the bonding position, and R ２４ is a hydrogen atom, a benzyl group, *-Si(R １８ )(R １９ )(R ２０ group (in the above formula, * represents the bonding position, and R １８ to R ２０ each independently represent an alkyl group having 1 to 4 carbon atoms or a phenyl group. ), or *-CO-R ２５ group (in the above formula, * represents the bonding position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ). ), a monovalent group represented by (viii) formula (xiv): (In formula (14), * represents the bonding position, and R ２６ and R ２７ is, independently of each other, a hydrogen atom, a benzyl group, or a *-Si(R １８ )(R １９ )(R ２０ ) group (in the above formula, * represents the bonding position, and R １８ to R ２０ each independently represents an alkyl group having 1 to 4 carbon atoms or a phenyl group.).), a monovalent group represented by (ix) Formula (15): (In Formula (15), * represents the bonding position, and R ２８ is a hydrogen atom, a benzyl group, or a *-Si(R １８ [[ID=I6]])(R １９ )(R ２０ ) group (in the above formula, * represents the bonding position, and R １８ to R ２０ each independently represents an alkyl group having 1 to 4 carbon atoms or a phenyl group.).), a monovalent group represented by (x) Formula (16): (In Formula (16), * represents the bonding position, R ２９ represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ３０ represents an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or an alkynyl group having 2 to 30 carbon atoms.).), a monovalent group represented by (xi) Formula (17): (In Formula (17), * represents the bonding position, and R ３１ represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ３２ and R ３３ each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms.).), a monovalent group represented by (xii) Formula (18): (In Formula (18), * represents the bonding position, R ３４ represents an alkylene group having 1 to 10 carbon atoms, and R ３５ and R ３６ Each of these independently represents an alkyl group having 1 to 10 carbon atoms.) A monovalent group represented by (xiii) an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or (xiv)R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p represents an integer from 1 to 8. (In equations (19a) and (19b), X ２ａ and X ２ｂ Each of these independently represents a hydroxyl group or a halogen atom, as well as na, nb, and Z. ａ Z ｂ , R ８ａ , and R ８ｂ This is as stated above.

12. A method for producing the compound represented by formula (20), comprising the following steps 4a to 4c: Step 4a: obtaining the compound represented by formula (5) by the production method described in claim 10; Step 4b: reacting the compound represented by formula (5), the compound represented by formula (21a), and the compound represented by formula (21b) to obtain the compound represented by formula (22); and Step 4c: deprotecting the compound represented by formula (22) to obtain the compound represented by formula (20). (In formula (20), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each of these independently represents an alkylene group having 1 to 8 carbon atoms or an oxydialkylene group having 2 to 8 carbon atoms, and Z ａ and Z ｂ Each of these independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, possessing at least one aromatic ring, and possibly containing a heteroatom. (In equations (21a) and (21b), X ３ａ and X ３ｂ Each of these independently represents a hydroxyl group or a halogen atom, Z ａ and Z ｂ As stated above, and also Pr １ and Pr ２ Each of these independently represents a protecting group for a hydroxyl group. (In formula (22), R １ａ , R １ｂ , X ａ , X ｂ , R ７ａ , R ７ｂ Z ａ Z ｂ , Pr １ , and Pr ２ This is as stated above.

13. A method for producing an ionic lipid represented by the following formula (7b), comprising the following steps 5a and 5b. Step 5a to obtain a compound represented by formula (20) by the manufacturing method described in claim 12, and step 5b to obtain an ionic lipid represented by formula (7b) by reacting the compound represented by formula (20), the compound represented by formula (23a), and the compound represented by formula (23b). (In formula (7b), R １ａ and R １ｂ Each of these independently represents an alkylene group with 1 to 6 carbon atoms, X ａ and X ｂ Each of these independently represents a cyclic or acyclic amino group having 1 or 2 nitrogen atoms and 1 to 10 carbon atoms, R ７ａ and R ７ｂ Each of these independently represents an alkylene group with 1 to 8 carbon atoms or an oxydialkylene group with 2 to 8 carbon atoms, Z ａ and Z ｂ Each independently represents a divalent group derived from an aromatic compound having 3 to 16 carbon atoms, having at least one aromatic ring, and possibly having a heteroatom, and R ８ａ and R ８ｂ Each of these independently comprises: (i) a monovalent group having 10 to 50 carbon atoms having one carbonyl group and at least one unsaturated bond selected from the group consisting of olefinic carbon-carbon double bonds and carbon-carbon triple bonds (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (ii) a monovalent group having 10 to 50 carbon atoms having at least two carbonyl groups (excluding monovalent groups containing residues of lipid-soluble vitamins having hydroxyl groups and residues of sterol derivatives having hydroxyl groups); (iii) formula (8): *-R ９ -X １ -R １０ (8) (In equation (8), * indicates the bonding position, R ９ X represents an alkylene group with 1 to 10 carbon atoms. １ R represents a carbamate bond, carbonate bond, or amide bond, and １０ represents an alkyl group having 1 to 25 carbon atoms, and R １０ (iv) Formula (9): *-R １１ -CO-O-R １２ (9) In equation (9), * represents the bonding position, R １１ R represents an alkylene group having 1 to 10 carbon atoms, and １２ represents an alkyl group having 1 to 25 carbon atoms that is substituted with at least one halogen atom. ) A monovalent group represented by formula (v) (10): (In equation (10), * represents the bond position, R １３ and R １４ Each of these independently represents an alkylene group with 1 to 10 carbon atoms, an alkenediyl group with 2 to 10 carbon atoms, or an alkynediyl group with 2 to 10 carbon atoms, R １５ ~R １７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (vi) Formula (11): (In equation (11), * represents the bonding position, X ２ is a nitrogen atom or formula (12): (In equation (12), * represents R ２１ This represents the bond position with, and ** is R ２２ or R ２３ This represents the bonding position with ( ). ) represents the trivalent group indicated by X ２ When R is a nitrogen atom, ２１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When is a trivalent group represented by formula (12), R ２１ R represents an alkylene group having 1 to 10 carbon atoms, and R ２１ X may be substituted with substituents selected from the group consisting of halogen atoms and hydroxyl groups. ２ When R is a nitrogen atom, ２２ and R ２３ Each independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups, and X ２ When is a trivalent group represented by formula (12), R ２２ and R ２３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, and R ２２ and R ２３ Each of these may be independently substituted with a substituent selected from the group consisting of halogen atoms and hydroxyl groups. ) A monovalent group represented by formula (vii) (13): (In formula (13), * represents the bond position, and R ２４ It consists of a hydrogen atom, a benzyl group, and *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ), or *-CO-R ２５ Base (In the above formula, * represents the bond position, R ２５ represents an alkyl group having 1 to 9 carbon atoms. ) represents a monovalent group represented by ), (viiii) formula (14): (In formula (14), * represents the bond position, and R ２６ and R ２７ Each of these independently consists of a hydrogen atom, a benzyl group, or *-Si(R) １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (ix) formula (15): (In formula (15), * represents the bond position, and R ２８ is a hydrogen atom, a benzyl group, or *-Si(R １８ ) (Caution １９ ) (Caution ２０ ) group (wherein * represents a bond position, and R １８ ~R ２０ Each of these independently represents an alkyl group or phenyl group having 1 to 4 carbon atoms. ) Represents a monovalent group represented by ), (x) Formula (16): (In formula (16), * represents the bonding position, R ２９ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３０ ) represents an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, or an alkynyl group having 2 to 30 carbon atoms. ) A monovalent group represented by formula (xi) (17): (In formula (17), * represents the bond position, and R ３１ R represents an alkylene group having 1 to 10 carbon atoms, an alkenediyl group having 2 to 10 carbon atoms, or an alkynediyl group having 2 to 10 carbon atoms, and ３２ and R ３３ Each of these independently represents an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or an alkynyl group having 2 to 10 carbon atoms. ) A monovalent group represented by formula (xii) (18): (In formula (18), * represents the bond position, R ３４ R represents an alkylene group having 1 to 10 carbon atoms, and ３５ and R ３６ Each of these independently represents an alkyl group having 1 to 10 carbon atoms.) A monovalent group represented by (xiii) an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, or an alkynyl group having 2 to 20 carbon atoms, wherein one ethylene group in the alkyl group may be replaced by one ester bond, or (xiv)R ８ｃ -CO-(CH ２ ) ｐ - Base (in the above formula, R ８ｃ represents a residue of a fat-soluble vitamin having a hydroxyl group or a residue of a sterol derivative having a hydroxyl group, and p represents an integer from 1 to 8. (In equations (23a) and (23b), X ４ａ and X ４ｂ Each of these independently represents a hydroxyl group or a halogen atom, and R ８ａ and R ８ｂ This is as stated above.

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