Lipids with amide and ester functional groups and methods for producing the same

Abstract

The present invention relates to lipids having amide and ester functional groups and a method for producing the same, and more specifically to ionizable lipids that form polyplexes with anionic drugs and are useful for drug delivery due to their specific structure having amide and ester functional groups, and a method for producing the same.

Description

[Technical Field]

[0001] The present invention relates to lipids having amide and ester functional groups and methods for preparing the same. More specifically, the present invention relates to ionizable lipids that form complexes with anionic drugs and are useful for drug delivery due to their specific structure having amide and ester functional groups, and methods for preparing the same. [Background technology]

[0002] Safe and efficient drug delivery technologies for treatment using anionic drugs, including nucleic acids, have long been studied, and various delivery vehicles and delivery technologies have been developed. Delivery vehicles are mainly divided into viral delivery vehicles using adenoviruses, retroviruses, etc., and non-viral delivery vehicles using cationic lipids, cationic polymers, etc. Viral delivery vehicles are known to pose many problems for commercialization due to risks such as non-specific immune responses and complex manufacturing processes. Therefore, recent research has been conducted toward improving these drawbacks by using non-viral delivery vehicles. Non-viral delivery vehicles have the advantages of fewer side effects in terms of safety in the body and lower manufacturing costs compared to viral delivery vehicles.

[0003] Representative non-viral delivery vehicles for delivering nucleic acid substances include cationic lipid-nucleic acid complexes (lipoplexes) and polycationic polymer-nucleic acid complexes (polyplexes). Such cationic lipids and polycationic polymers form complexes with anionic drugs through electrostatic interactions, stabilizing the anionic drugs and increasing their intracellular delivery, and thus have been the subject of extensive research (Non-Patent Documents 1 and 2).

[0004] However, polycationic polymers have cytotoxicity due to their multivalent cationic charge, making their practical application problematic. Furthermore, nucleic acid-cationic lipid complexes have low stability in the blood, making their in vivo use difficult. Furthermore, ionic liposomes containing cationic lipids, neutral lipids, and fusogenic lipids have drawbacks, such as the complex synthesis of the cationic lipids used, cytotoxicity, and low efficiency of intracellular nucleic acid delivery. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56 [Non-patent document 2] Gary DJ, Puri N, Won YY, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J Control release 121 (2007) 64-73 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a lipid having a specific structure that can easily form a complex with an anionic drug and is useful for drug delivery, and a method for producing the same. [Means for solving the problem]

[0007] A first aspect of the present invention provides a lipid having a structure or an ionized form thereof selected from the following: [ka] wherein in said structure at least two of the R groups are Rx and the remaining R groups are Ry; where Rx is independently [ka] is selected from wherein a, b, and c each independently represent an integer of 2 to 20; R1 represents a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 represents a substituted or unsubstituted, unsaturated monovalent hydrocarbon group. [ka] represents a substituted or unsubstituted methylene group, each Ry is independently H or a substituted or unsubstituted alkyl group, and two Ry groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently a substituted or unsubstituted alkylene group, which may optionally have an ether bond (-O-), a thioether bond (-S-), or a disulfide bond (-SS-) in its structure.

[0008] According to one embodiment of the present invention, each Ry is independently H or C. 1-20 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —OH, C 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0009] According to one embodiment of the present invention, each L is independently C 1-20 alkylene groups, each independently unsubstituted or substituted with —OH, C 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S. The heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S. More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer of 2 to 20 or 2 to 15; R1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 may be a hydrocarbon group, [ka] represents a substituted or unsubstituted methylene group.

[0010] More specifically, each Ry is independently H or C. 1-10 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —OH, C 1-10 Alkyl, C 1-10Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0011] More specifically, each L is independently C 1-10 alkylene groups, each independently unsubstituted or selected from the group consisting of —OH, C 1-10 Alkyl, C 1-10 Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S. The heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0012] More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer from 3 to 12; and R1 is selected from the group consisting of substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 R2 may be a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 may be an alkynyl group, [ka] represents a substituted or unsubstituted methylene group.

[0013] More specifically, each Ry is independently H or C. 1-6 and alkyl groups, wherein the alkyl groups are independently unsubstituted or substituted with one or more selected from -OH and -NH, and two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0014] More specifically, each L is independently an unsubstituted C 1-6 It may also be an alkylene group.

[0015] More specifically, the lipid may have a structure selected from the following formulas (A-V):

[0016] [Table 1-1]

[0017] [Table 1-2]

[0018] [Table 1-3]

[0019] A second aspect of the present invention relates to a method for producing a pharmaceutical composition comprising the steps of: (1) reacting a compound of formula (a) with a compound of formula (b) to obtain a compound of formula (c); (2) reacting a compound of formula (c) with a compound of formula (d) to obtain a compound of formula (e); and (3) reacting a compound of formula (e) with a compound of formula (f) and deprotecting the reaction product The present invention provides a method for producing a lipid having a structure represented by formula (1-1), comprising:

[0020] Formula (a) is H2N-(CH2) a -C(=O)OH, Formula (b) is OH-R', Formula (c) is H2N-(CH2) a -C(=O)O-R', Equation (d) is [ka] and Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (f) is H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3, Formula (1-1) is H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0021] A third aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1-2), comprising the step of reacting a compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (g):

[0022] Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (g) is H2N-(CH2) 1-20 -N(C 1-20 alkyl)2, Equation (1-2) is (C 1-20 alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, and a, b, and c are each independently an integer of 2 to 20.

[0023] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1-3), comprising the step of reacting a compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (h):

[0024] Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (h) is (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl), Equation (1-3) is AN(C 1-10 alkyl)-(CH2) 1-20 -N(C 1-10 alkyl)-A. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, A is -CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R', a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0025] A fifth aspect of the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (1) reacting a compound of formula (a) with a compound of formula (b') to obtain a compound of formula (c'); (2) reacting a compound of formula (c') with a compound of formula (d) to obtain a compound of formula (e'); and (3) reacting the compound of formula (e') with the compound of formula (h) The present invention provides a method for producing a lipid having a structure represented by formula (1-4), comprising:

[0026] Formula (a) is H2N-(CH2) a -C(=O)OH, Formula (b') is OH-R2, Formula (c') is H2N-R1-C(=O)O-R2, Equation (d) is [ka] and Formula (e') is H2C=CH-C(=O)-HN-R1-C(=O)O-R2, Formula (h) is (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl), Equation (1-4) is A'-N(C 1-10 alkyl)-(CH2) 1-20-N(C1-10 alkyl)-A'. (In the formula, A' is -CH2-CH2-C(=O)-HN-R1-C(=O)O-R2, R1 is independently a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R2 is independently a substituted or unsubstituted, unsaturated monovalent hydrocarbon group, a is an integer of 2 to 20, and X is selected from the group consisting of F, CI, Br, and I.)

[0027] A sixth aspect of the present invention provides a drug delivery composition comprising a lipid according to the present invention. [Effects of the Invention]

[0028] The lipids with specific structures according to the present invention can easily form complexes with anionic drugs, and by utilizing these complexes, drugs can be efficiently delivered to target biological tissues. [Brief explanation of the drawings]

[0029] [Figure 1] 1 is a reaction scheme for the lipid synthesis process carried out in Example 1. [Figure 2] 1 is a reaction scheme for the lipid synthesis process carried out in Example 2. [Figure 3] 1 is a reaction scheme for the lipid synthesis process carried out in Example 3. [Figure 4] 1 is a reaction scheme for the lipid synthesis process carried out in Example 4. [Figure 5] 1 is a reaction scheme for the lipid synthesis process carried out in Example 5. [Figure 6] 1 is a reaction scheme for the lipid synthesis process carried out in Example 6. [Figure 7] 1 is a reaction scheme for the lipid synthesis process carried out in Example 7. [Figure 8] 1 is a reaction scheme for the lipid synthesis process carried out in Example 8. [Figure 9] 1 is a reaction scheme for the lipid synthesis process carried out in Example 9. [Figure 10]1 is a reaction scheme for the lipid synthesis process carried out in Example 10. [Figure 11] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 11. [Figure 12] 1 is a reaction scheme for the lipid synthesis process carried out in Example 12. [Figure 13] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 13. [Figure 14] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 14. [Figure 15] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 15. [Figure 16] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 16. [Figure 17] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 17. [Figure 18] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 18. [Figure 19] 1 shows a reaction scheme for the lipid synthesis process carried out in Example 19. [Figure 20] 1 is a reaction scheme for the lipid synthesis process carried out in Example 20. [Figure 21] 1 is a reaction scheme for the lipid synthesis process carried out in Example 21. [Figure 22] 1 is a reaction scheme for the lipid synthesis process carried out in Example 22. BEST MODE FOR CARRYING OUT THE INVENTION

[0030] The present invention will now be described in further detail. The lipids provided by the first aspect of the present invention have a structure selected from the following, or in their ionized form: [ka]

[0031] (wherein in each of the structures, at least two (more specifically, 2 to 7) of the R groups are Rx, and the remaining R groups are Ry; Rx is independently [ka] wherein a, b, and c are each independently an integer of 2 to 20; R1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 is a substituted or unsubstituted, unsaturated monovalent hydrocarbon group; [ka] represents a substituted or unsubstituted methylene group, each Ry is independently H or a substituted or unsubstituted alkyl group, and two Ry groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently a substituted or unsubstituted alkylene group, which may optionally have an ether bond (-O-), a thioether bond (-S-), or a disulfide bond (-SS-) in its structure.

[0032] In this specification, the expression "substituted or unsubstituted" for any group means that the group is not substituted or is substituted with an -OH, halogen atom, C, or C, unless otherwise specified. 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 3-20 Cycloalkyl groups, C 3-20 Heterocycloalkyl groups, C 6-20 Aryl group or C 3-20 It means that the group is substituted with one or more substituents selected from heteroaryl groups.

[0033] According to one embodiment of the present invention, each Rx is independently [ka] wherein a, b, and c may each independently be an integer of 2 to 20 or 2 to 15; R1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 may be a hydrocarbon group, [ka] represents a substituted or unsubstituted methylene group.

[0034] According to one embodiment of the present invention, a, b, and c may each independently be an integer of 2 to 15, more specifically, may each independently be an integer of 3 to 12. Even more specifically, a may be an integer of 5 to 7, and b and c may each independently be an integer of 3 to 11, but are not limited thereto.

[0035] According to one embodiment of the present invention, each Ry is independently H or C. 1-20 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —OH, C 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic groups (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl groups) and optionally substituted C 3-20 Heterocyclic groups (e.g., C 3-20 Heterocycloalkyl group or C 3-20 heteroaryl groups), wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S, and two R groups other than H may be linked together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O. In addition, the alkyl group or alkoxy group may more specifically be C1-10 Alkyl or alkoxy groups, more specifically C 1-6 It may be, but is not limited to, an alkyl group or an alkoxy group.

[0036] According to one embodiment of the present invention, each L is independently C 1-20 Alkylene groups (more specifically, C 1-10 Alkylene groups, more specifically C 1-6 alkylene groups), each independently unsubstituted or 1-20 Alkyl, C 1-20 Alkoxy, -NH2, -NH(C 1-20 alkyl), -N(C 1-20 alkyl)2, optionally substituted C 3-20 Carbocyclic groups (e.g., C 3-20 Cycloalkyl group or C 6-20 aryl groups) and optionally substituted C 3-20 Heterocyclic groups (e.g., C 3-20 Heterocycloalkyl group or C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S (e.g., 1 to 3). The alkyl or alkoxy group may be, more specifically, C 1-10 Alkyl or alkoxy groups, more specifically C 1-6 It may be, but is not limited to, an alkyl group or an alkoxy group.

[0037] More specifically, each Ry is independently H or C. 1-10 alkyl groups, where the alkyl groups are independently unsubstituted or selected from the group —OH, C 1-10 Alkyl, C 1-10 Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10The heterocyclic group may be substituted with one or more heteroatoms selected from N, O, and S, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0038] More specifically, each L is independently C 1-10 alkylene groups, each independently unsubstituted or selected from the group consisting of —OH, C 1-10 Alkyl, C 1-10 Alkoxy, -NH2, -NH(C 1-10 alkyl), -N(C 1-10 alkyl)2, optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 It may be substituted with one or more heterocyclic groups, wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0039] More specifically, each Rx is independently [ka] wherein a, b, and c may each independently be an integer from 3 to 12; and R1 is selected from the group consisting of substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 R2 may be a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 may be an alkynyl group, [ka] represents a substituted or unsubstituted methylene group.

[0040] More specifically, each Ry is independently H or C. 1-6 and R may be an alkyl group, wherein the alkyl groups are independently unsubstituted or substituted with one or more selected from -OH and -NH, and two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure optionally having one or more heteroatoms selected from N and O.

[0041] More specifically, each L is independently an unsubstituted C 1-6 It may also be an alkylene group.

[0042] Specifically, the lipid may have a structure selected from the following: [ka]

[0043] In each of the above structures, R1 to R7 are each independently [ka] wherein a, b, and c are each independently an integer of 2 to 20; R1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group; and R2 is a substituted or unsubstituted, unsaturated monovalent hydrocarbon group; [ka] represents a substituted or unsubstituted methylene group.

[0044] More specifically, the lipid may have a structure selected from the following formulas (A-V):

[0045] [Table 2-1]

[0046] [Table 2-2]

[0047] [Table 2-3]

[0048] A second aspect of the present invention relates to a method for producing a pharmaceutical composition comprising the steps of: (1) reacting a compound of formula (a) with a compound of formula (b) to obtain a compound of formula (c); (2) reacting a compound of formula (c) with a compound of formula (d) to obtain a compound of formula (e); and (3) reacting a compound of formula (e) with a compound of formula (f) and deprotecting the reaction product The present invention provides a method for producing a lipid having a structure represented by formula (1-1), comprising:

[0049] Formula (a) is H2N-(CH2) a -C(=O)OH, Formula (b) is OH-R', Formula (c) is H2N-(CH2) a -C(=O)O-R', Equation (d) is [ka] and Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (f) is H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3, Equation (1-1) is H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0050] In one embodiment of the lipid production method according to the second aspect of the present invention, the reaction in step (1) can be carried out in a solvent (e.g., cyclohexane) in the presence of a catalyst (e.g., p-toluenesulfonic acid monohydrate (p-TsOH)) under reflux, the reaction in step (1) can be carried out in a solvent (e.g., methylene chloride (MC)) in the presence of a catalyst (e.g., triethylamine (TEA)) at low temperature (e.g., -10°C to 10°C) or room temperature (e.g., 20°C to 30°C), the reaction in step (3) can be carried out in a solvent (e.g., N-butanol (n-BuOH)) under reflux, and the deprotection in step (3) can be carried out in a solvent (e.g., methylene chloride (MC)) in the presence of an acid (e.g., trifluoroacetic acid (TFA)) at room temperature (e.g., 20°C to 30°C), but is not limited thereto.

[0051] A third aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1-2), comprising the step of reacting a compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (g):

[0052] Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (g) is H2N-(CH2) 1-20 -N(C 1-20 alkyl)2, Equation (1-2) is (C 1-20 alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, and a, b, and c are each independently an integer of 2 to 20.

[0053] In one embodiment of the method for producing lipids according to the third aspect of the present invention, the reaction can be carried out under reflux in a solvent (for example, n-butanol (n-BuOH)), but is not limited thereto.

[0054] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1-3), comprising the step of reacting a compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (h):

[0055] Formula (e) is H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R', Formula (h) is (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl), Equation (1-3) is AN(C 1-10 alkyl)-(CH2) 1-20 -N(C 1-10 alkyl)-A. (In the formula, each R' is independently [ka] where * represents the point of attachment to the adjacent oxygen atom; [ka] represents a substituted or unsubstituted methylene group, A is -CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R', a, b, and c each independently represent an integer of 2 to 20; X is selected from the group consisting of F, CI, Br and I.

[0056] In one embodiment of the method for producing lipids according to the fourth aspect of the present invention, the reaction can be carried out under reflux in a solvent (for example, n-butanol (n-BuOH)), but is not limited thereto.

[0057] A fifth aspect of the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (1) reacting a compound of formula (a) with a compound of formula (b') to obtain a compound of formula (c'); (2) reacting a compound of formula (c') with a compound of formula (d) to obtain a compound of formula (e'); and (3) reacting the compound of formula (e') with the compound of formula (h) and a method for producing a lipid having a structure represented by formula (1-4), comprising:

[0058] Formula (a) is H2N-(CH2) a -C(=O)OH, Formula (b') is OH-R2, Formula (c') is H2N-R1-C(=O)O-R2, Equation (d) is [ka] and Formula (e' is H2C=CH-C(=O)-HN-R1-C(=O)O-R2, Formula (h) is (C 1-10 alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl), Equation (1-4) is A'-N(C 1-10 alkyl)-(CH2) 1-20 -N(C 1-10 alkyl)-A'. (In the formula, A' is -CH2-CH2-C(=O)-HN-R1-C(=O)O-R2, R1 is independently a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R2 is independently a substituted or unsubstituted, unsaturated monovalent hydrocarbon group, a is an integer of 2 to 20, and X is selected from the group consisting of F, CI, Br, and I.)

[0059] In one embodiment of the method for producing lipid according to the fifth aspect of the present invention, the reaction in step (1) is carried out in a solvent (e.g., cyclohexane) in the presence of a catalyst (e.g., p-toluenesulfonic acid monohydrate (p-TsOH)) under reflux, the reaction in step (2) is carried out in a solvent (e.g., methylene chloride (MC)) in the presence of a catalyst (e.g., triethylamine (TEA)) at low temperature (e.g., −10° C. to 10° C.) or room temperature (e.g., 20° C. to 30° C.), and the reaction in step (3) can be carried out in a solvent (e.g., N-butanol (n-BuOH)) under reflux, but is not limited thereto.

[0060] The lipids having a specific structure according to the present invention are useful for drug delivery because they can easily form complexes with anionic drugs. Therefore, according to a sixth aspect of the present invention, there is provided a drug delivery composition comprising the lipid of the present invention. In one embodiment, the drug may be selected from a nucleic acid, a polypeptide, a virus, or a combination thereof.

[0061] The "nucleic acid" may be, for example, but is not limited to, DNA, RNA, siRNA, shRNA, miRNA, mRNA, an aptamer, an antisense oligonucleotide, or a combination thereof.

[0062] The term "polypeptide" may refer to a protein that has activity in the body, such as an antibody or a fragment thereof, a cytokine, a hormone or an analog thereof, or a protein that can be recognized as an antigen through a series of processes in the body, including the polypeptide sequence of an antigen, an analog thereof, or a precursor thereof.

[0063] In one embodiment, the lipids of the present invention are complexed with a drug, and the complex is encapsulated within the nanoparticle structure formed by the amphiphilic block copolymer.

[0064] In one embodiment, the amphiphilic block copolymer may be an AB type block copolymer comprising a hydrophilic A block and a hydrophobic B block, which in an aqueous environment forms core-shell polymeric nanoparticles in which the hydrophobic B block forms the core (inner wall) and the hydrophilic A block forms the shell (outer wall).

[0065] In one embodiment, the hydrophilic A block may be one or more selected from the group consisting of polyalkylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, and derivatives thereof.

[0066] More specifically, the hydrophilic A block may be one or more selected from the group consisting of monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, a copolymer of polyethylene and propylene glycol, and polyvinylpyrrolidone.

[0067] Furthermore, if necessary, functional groups, ligands, or functional groups capable of targeting specific tissues or cells, or functional groups capable of promoting intracellular delivery, can be chemically bonded to the ends of the hydrophilic A block to control the biodistribution of polymeric nanoparticle delivery vehicles formed from amphiphilic block copolymers and polylactic acid salts or to enhance the intracellular delivery efficiency of the nanoparticle delivery vehicles. In one embodiment, the functional group or ligand may be one or more selected from the group consisting of monosaccharides, polysaccharides, vitamins, peptides, proteins, and antibodies against cell surface receptors. More specifically, the functional group or ligand may be one or more selected from the group consisting of anisamide, vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, antibodies against transferrin receptors, and the like.

[0068] The hydrophobic B block is a biocompatible, biodegradable polymer, which in one embodiment may be one or more selected from the group consisting of polyesters, polyanhydrides, polyamino acids, polyorthoesters, and polyphosphazines.

[0069] More specifically, the hydrophobic B block may be one or more selected from the group consisting of polylactide (PLA), polyglycolide, polycaprolactone, polydioxane-2-one, a copolymer of polylactide and glycolide, a copolymer of polylactide and polydioxane-2-one, a copolymer of polylactide and polycaprolactone, and a copolymer of polyglycolide and polycaprolactone.

[0070] In one embodiment, in order to increase the hydrophobicity of the hydrophobic B block and thereby improve the stability of the nanoparticles, the hydrophobic B block may be modified by chemically bonding tocopherol, cholesterol, or a fatty acid having 10 to 24 carbon atoms to the hydroxy group at the end of the hydrophobic B block.

[0071] The present invention will be described in more detail below with reference to examples. However, these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. [Example]

[0072] Example 1 1-1. The compound of formula (A) below was produced according to the synthesis scheme shown in FIG. [ka]

[0073] 1-2. Synthesis of undecyl 6-acrylamidohexanoate A 250 mL three-neck round-bottom flask (RBF) was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), undecane-1-ol (11.94 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the reaction mixture was concentrated under vacuum and extracted with methylene chloride (MC) and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain low-purity undecyl 6-aminohexanoate. Without further purification, the previously obtained undecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After that, acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified using a silica column with ethyl acetate:hexane (1:1) to obtain undecyl 6-acrylamidohexanoate (17.22 g, yield: 73%).

[0074] 1 H-NMR (400 MHz, CDCl3) δ 6.25 (dd, 1H), 6.01-6.08 (m, 1H), 5.61-5.68 (m, 2H), 4.01 (t, 2H), 3.31 (q, 2H), 2.28 (t, 2H), 1.43-1.68 (m, 6H), 1.30-1.45 (m, 18H), 0.89 (t, 3H)

[0075] 1-3. Synthesis of undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate

[0076] A 100 mL single-neck RBF was charged with undecyl 6-acrylamidohexanoate (3 g, 8.83 mmol, 3 eq), tert-butyl (2-aminoethyl)carbamate (0.47 g, 2.94 mmol, 1 eq), and n-butanol (n-BuOH) (40 mL) and stirred at reflux. After 4 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate (1.34 g, 54% yield).

[0077] 1 H-NMR (400 MHz, CDCl3) δ 4.06 (t, 4H), 3.49 (q, 4H), 3.26-3.16 (br, 2H), 2.71 (q, 4H), 2.48-2.41 (br, 2H), 2.32-2.85 (m, 8H), 1.67-1.26 (m, 48H), 1.44 (s, 9H), 0.87 (t, 6H)

[0078] 1-4. Synthesis of Compound of Formula (A) To a 100 mL single-neck RBF, undecyl 2,2-dimethyl-4,11-dioxo-8-(3-oxo-3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)-3-oxa-5,8,12-triazaoctadecane-18-oate (1 g, 1.19 mmol) and methylene chloride (20 mL) were added, and trifluoroacetic acid (TFA) (2 mL) was added dropwise. After stirring at room temperature for 4 hours, the mixture in the reactor was extracted with saturated aqueous sodium bicarbonate, and the methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound of formula (A) (0.31 g, 35%).

[0079] 1 H-NMR (400 MHz, CDCl3) δ 6.86 (t, 2H), 4.06 (t, 4H), 3.25 (t, 4H), 2.89 (t, 2H), 2.68 (t, 4H), 2.58 (t, 2H), 2.36 (t, 4H), 2.31 (t, 2H), 1.65 - 1.26 (m, 48H), 0.89 (t, 6H)

[0080] Example 2 2-1. The compound of formula (B) below was produced according to the synthesis scheme shown in FIG. [ka]

[0081] Synthesis of 2-2,2-hexyldecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), 2-hexyldecan-1-ol (16.80 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-hexyldecyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyldecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After that, acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using ethyl acetate:hexane (1:1) to obtain 2-hexyldecyl 6-acrylamidohexanoate (14.25 g, yield: 50%).

[0082] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.07-6.12 (m, 1H), 5.62-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 5H), 1.26-1.41 (m, 26H), 0.87 (t, 6H)

[0083] Synthesis of 2-3,2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate

[0084] 2-Hexyldecyl 6-acrylamidohexanoate (4 g, 9.76 mmol, 3 eq), tert-butyl (2-aminoethyl)carbamate (0.52 g, 3.25 mmol, 1 eq), and n-butanol (n-BuOH) (40 mL) were added to a 100 mL single-neck RBF and stirred at reflux. After 4 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give 2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (2.23 g, 70% yield).

[0085] 1 H-NMR (400 MHz, CDCl3) δ 7.09 (br, 2H), 3.96 (d, 4H), 3.35 (q, 4H), 3.26 (q, 4H), 3.06 (br, 4H), 2.88 (t, 4H), 2.50 (br, 4H), 2.32 (t, 4H), 1.67-1.35 (m, 62H), 1.44 (s, 9H), 0.89 (t, 12H)

[0086] 2-4. Synthesis of Compound of Formula (B) To a 100 mL single-neck RBF, 2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (2 g, 2.04 mmol) and methylene chloride (40 mL) were added, and trifluoroacetic acid (TFA) (4 mL) was added dropwise. After stirring at room temperature for 4 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound of formula (B) (1.21 g, 67%).

[0087] 1 H-NMR (400 MHz, CDCl3) δ 6.96 (t, 2H), 3.96 (t, 4H), 3.21 - 3.13 (m, 6H), 2.71 (t, 2H), 2.64 (t, 4H), 2.37 (t, 4H), 2.31 (t, 4H), 1.65 - 1.33 (m, 62H), 0.89 (t, 6H)

[0088] Example 3 3-1. A compound of the following formula (C) was produced according to the synthesis scheme shown in FIG. [ka]

[0089] 3-2. Synthesis of compound of formula (C) 2-Hexyldecyl 6-acrylamidohexanoate (3 g, 7.32 mmol, 3 eq) synthesized in Example 2-2, N,N-dimethylethylenediamine (0.22 g, 2.44 mmol, 1 eq), and N-butanol (n-BuOH) (30 mL) were added to a 100 mL single-neck RBF and refluxed with stirring. After 3 days, the mixture was concentrated under vacuum at 70 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (C) (0.95 g, 43% yield).

[0090] 1 H-NMR (400 MHz, CDCl3) δ 4.05 (t, 4H), 3.15 (q, 4H), 2.77 (br, 4H), 2.69 (t, 4H), 2.53 (br, 6H), 2.12 (t, 4H), 2.28 (t, 4H), 1.66 - 1.26 (m, 62H), 0.89 (t, 6H)

[0091] Example 4 4-1. A compound of the following formula (D) was produced according to the synthesis scheme shown in FIG. [ka]

[0092] Synthesis of 4-2,2-butyloctyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (5.03 g, 38.32 mmol, 1.20 eq), 2-butyl-1-n-octanol (5.95 g, 31.93 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (10.93 g, 57.48 mmol, 1.80 eq), and cyclohexane (200 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-butyloctyl 6-aminohexanoate. Without further purification, the previously obtained 2-butyloctyl 6-aminohexanoate, methylene chloride (170 mL), and triethylamine (7.11 g, 70.28 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (3.18 g, 35.12 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using ethyl acetate (EtOAc):hexane (1:2) to obtain 2-butyloctyl 6-acrylamidohexanoate (5.0 g, yield: 44%).

[0093] 1 H-NMR (400 MHz, CDCl3) δ 6.47 (dd, 1H), 6.09-6.15 (m, 1H), 5.63 (dd, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 6H), 1.27-1.40 (m, 20H), 0.87-0.91 (m, 6H)

[0094] 4-3. Synthesis of Compound of Formula (D) 2-Butyloctyl 6-acrylamidohexanoate (1000.00 mg, 2.83 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (111.16 mg, 1.09 mmol, 1.00 eq), and n-BuOH (11 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound (D) (712.60 mg, 81% yield).

[0095] 1 H-NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.61 (t, 4H), 2.41 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.70 (m, 8H), 1.48-1.54 (m, 4H), 1.25-1.39 (m, 37H), 0.90 (t, 3H)

[0096] Example 5 5-1. The compound of formula (E) below was produced according to the synthesis scheme shown in FIG. [ka]

[0097] Synthesis of 5-2,2-hexyloctyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (1.84 g, 13.99 mmol, 1.20 eq), 2-hexyl-1-n-octanol (2.50 g, 11.66 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.99 g, 20.99 mmol, 1.80 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-hexyloctyl 6-aminohexanoate. Without further purification, the previously obtained 2-hexyloctyl 6-aminohexanoate, methylene chloride (60 mL), triethylamine (2.60 g, 25.65 mmol, 2.20 eq), and methylene chloride (60 mL) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (1.16 g, 12.83 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-hexyloctyl 6-acrylamidohexanoate (3.63 g, 82% yield).

[0098] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.11 (m, 1H), 5.63 (dd, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.41-1.68 (m, 6H), 1.21-1.41 (m, 20H), 0.85-0.90 (m, 6H)

[0099] 5-3. Synthesis of Compound of Formula (E) 2-Hexyloctyl 6-acrylamidohexanoate (660.27 mg, 1.73 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (68.00 mg, 0.67 mmol, 1.00 eq), and n-BuOH (7 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound (E) (375.60 mg, 65% yield). 1 H-NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.71 (m, 8H), 1.48-1.54 (m, 4H), 1.20-1.40 (m, 45H), 0.90 (t, 12H)

[0100] Example 6 6-1. A compound of the following formula (F) was produced according to the synthesis scheme shown in FIG. [ka]

[0101] 6-2. Synthesis of butyl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (6.37 g, 48.57 mmol, 1.20 eq), butan-1-ol (3.00 g, 40.47 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (15.40 g, 80.95 mmol, 2.00 eq), and cyclohexane (200 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure butyl 6-aminohexanoate. Without further purification, the previously obtained butyl 6-aminohexanoate, methylene chloride (200 mL), and triethylamine (9.01 g, 89.04 mmol, 2.20 eq) were added to a 500 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (4.03 g, 44.52 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to give butyl 6-acrylamidohexanoate (3.58 g, yield: 37%).

[0102] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.01-6.11 (m, 1H), 5.62-5.67 (m, 2H), 4.07 (t, 2H), 3.34 (q, 2H), 2.31 (t, 2H), 1.41-1.62 (m, 6H), 1.34-1.39 (m, 4H), 0.93 (t, 3H)

[0103] 6-3. Synthesis of Compound of Formula (F) A 100 mL three-necked RBF was charged with butyl 6-acrylamidohexanoate (700.00 mg, 2.90 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (113.99 mg, 1.12 mmol, 1.00 eq), and N-BuOH (11 mL) and stirred under reflux. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound of formula (F) (479.00 mg, 73% yield).

[0104] 1 H-NMR (400 MHz, CDCl3) δ 7.89 (s, 2H), 4.06 (t, 4H), 3.22 (q, 4H), 2.61 (t, 4H), 2.46 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.31 (s, 6H), 1.60-1.70 (m, 10H), 1.41-1.60 (m, 4), 1.32-1.39 (m, 8H), 0.90 (t, 6H)

[0105] Example 7 7-1. The compound of formula (G) below was produced according to the synthesis scheme shown in FIG. [ka]

[0106] Synthesis of 7-2,2-octyldodecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (1.05 g, 8.04 mmol, 1.20 eq), 2-octyldodecan-1-ol (2.00 g, 6.70 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (2.29 g, 12.06 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-octyldodecyl 6-aminohexanoate. Without further purification, the previously obtained 2-octyldodecyl 6-aminohexanoate, methylene chloride (33 mL), and triethylamine (1.49 g, 14.74 mmol, 2.20 eq) were added to a 100 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (0.67 g, 7.37 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-octyldodecyl 6-acrylamidohexanoate (1928.20 mg, yield: 62%).

[0107] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.59-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H), 2.32 (t, 2H), 1.54-1.68 (m, 4H), 1.26-1.41 (m, 36H), 0.89 (t, 6H)

[0108] 7-3. Synthesis of Compound of Formula (G) 2-Octyldodecyl 6-acrylamidohexanoate (592.57 mg, 1.27 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (50.00 mg, 0.49 mmol, 1.00 eq), and n-BuOH (5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (G) (346.8 mg, 69% yield).

[0109] 1 H-NMR (400 MHz, CDCl3) δ 7.83 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.69 (m, 8H), 1.48-1.54 (m, 4H), 1.25-1.39 (m, 69H), 0.90 (t, 3H)

[0110] Example 8 8-1. The compound of formula (H) below was produced according to the synthesis scheme shown in FIG. [ka]

[0111] Synthesis of 8-2,2-hexyloctyl 8-acrylamidooctanoate A 250 mL three-neck RBF was charged with 8-aminooctanoic acid (1.78 g, 11.19 mmol, 1.20 eq), 2-hexyloctan-1-ol (2.00 g, 9.33 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (3.19 g, 16.79 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure 2-hexyloctyl 8-aminooctanoate. Without further purification, the previously obtained 2-hexyloctyl 8-aminooctanoate, methylene chloride (100 mL), and triethylamine (2.08 g, 20.52 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (0.93 g, 10.26 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to obtain 2-hexyloctyl 8-acrylamidooctanoate (2838.70 mg, 74% yield).

[0112] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.55-5.64 (m, 2H), 3.97 (d, 2H), 3.32 (q, 2H), 2.29 (t, 2H), 1.51-1.65 (m, 4H), 1.27-1.35 (m, 27H), 0.85-0.90 (m, 6H)

[0113] 8-3. Synthesis of Compound of Formula (H) 2-Hexyloctyl 8-acrylamidooctanoate (703.42 mg, 0.76 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (30.00 mg, 0.29 mmol, 1.00 eq), and n-BuOH (5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (H) (218.90 mg, 81% yield).

[0114] 1 H-NMR (400 MHz, CDCl3) δ 7.78 (s, 2H), 3.96 (d, 4H), 3.21 (q, 4H), 2.64 (t, 4H), 2.44 (t, 4H), 2.38 (t, 4H), 2.28-2.32 (m, 4H), 2.26 (s, 6H), 1.66-1.72 (m, 2H), 1.40-1.63 (m, 10H), 1.20-1.40 (m, 54H), 0.90 (t, 12H)

[0115] Example 9 9-1. The compound of formula (I) below was produced according to the synthesis scheme shown in FIG. [ka]

[0116] Synthesis of 9-2,2-decyltetradecyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (887.70 mg, 6.77 mmol, 1.20 eq), 2-decyltetradecane-1-ol (2.00 g, 5.64 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (1.93 g, 10.15 mmol, 1.80 eq), and cyclohexane (100 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-decyltetradecyl 6-aminohexanoate. Without further purification, the previously obtained 2-decyltetradecyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (1.26 g, 12.41 mmol, 2.20 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (561.44 mg, 6.20 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain 2-decyltetradecyl 6-acrylamidohexanoate (1.29 g, yield: 44%).

[0117] 1 H-NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.10 (m, 1H), 5.62-5.64 (m, 2H), 3.97 (d, 2H), 3.34 (q, 2H) 2.31 (t, 2H), 1.54-1.68 (m, 5H), 1.26-1.41 (m, 44H), 0.88-0.89 (m, 6H)

[0118] 9-3. Synthesis of Compounds of Formula (I) 2-Decyltetradecyl 6-acrylamidohexanoate (306.44 mg, 0.59 mmol, 2.40 eq), N,N'-dimethyl-1,3-propanediamine (25.00 mg, 0.24 mmol, 1.00 eq), and n-BuOH (2.5 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give the compound of formula (I) (209.2 mg, 75% yield).

[0119] 1 H-NMR (400 MHz, CDCl3) δ 7.86 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.60 (t, 4H), 2.41 (t, 4H), 2.35 (t, 4H), 2.30 (t, 4H), 2.24 (s, 6H), 1.61-1.69 (m, 11H), 1.48-1.53 ​​(m, 4H), 1.20-1.40 (m, 87H), 0.9 (t, 12H)

[0120] Example 10 10-1. The compound of formula (J) below was produced according to the synthesis scheme shown in FIG. [ka]

[0121] 10-2. Synthesis of Compound of Formula (J) 2-Hexyldecyl 6-acrylamidohexanoate (2000.00 mg, 4.88 mmol, 3.00 eq) synthesized in Example 2-2, N,N'-dimethyl-1,3-propanediamine (170.00 mg, 1.63 mmol, 1.00 eq), and N-BuOH (20 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (J) (934.00 mg, yield: 62%).

[0122] 1 H-NMR (400 MHz, CDCl3) δ 7.88 (s, 2H), 3.96 (d, 4H), 3.22 (q, 4H), 2.60 (t, 4H), 2.40 (t, 4H), 2.35 (t, 4H), 2.30 (t, 4H), 2.27 (s, 6H), 1.61-1.70 (m, 8H), 1.40-1.54 (m, 4H), 1.20-1.40 (m, 52H), 0.90 (t, 12H)

[0123] Example 11 11-1. The compound of formula (K) below was produced according to the synthesis scheme shown in FIG. [ka]

[0124] 11-2. Synthesis of nonyl 6-acrylamidohexanoate A 250 mL three-neck RBF was charged with 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 eq), nonan-1-ol (21.58 g, 69.30 mmol, 1 eq), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 eq), and cyclohexane (120 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was concentrated in vacuo and extracted with methylene chloride and 3% aqueous sodium hydroxide. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give low-purity nonyl 6-aminohexanoate. Without further purification, the previously obtained nonyl 6-aminohexanoate, methylene chloride (100 mL), and triethylamine (15.43 g, 152.46 mmol, 2.2 eq) were added to a 250 mL three-neck RBF and cooled to 0 °C. Acryloyl chloride (6.90 g, 76.23 mmol, 1.1 eq) was then added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 4 h, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:1) to give nonyl 6-acrylamidohexanoate (15.66 g, yield: 66%).

[0125] 1 H-NMR (400 MHz, CDCl3) δ 6.28 (d, 1H), 6.11 (m, 1H), 5.64 (d, 2H), 4.07 (t, 2H), 3.63 (q, 2H), 2.32 (t, 2H), 1.68 - 1.26 (m, 20H), 0.90 (t, 3H)

[0126] 11-3. Synthesis of Compound of Formula (K) Nonyl 6-acrylamidohexanoate (1000.00 mg, 3.21 mmol, 2.60 eq), N,N'-dimethyl-1,3-propanediamine (126.18 mg, 1.23 mmol, 1.00 eq), and N-BuOH (10 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound (K) (770.10 mg, 86% yield). 1 H-NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 4.05 (t, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.42 (t, 4H), 2.36 (t, 2H), 2.30 (t, 4H), 2.25 (s, 6H), 1.61-1.69 (m, 10H), 1.40-1.60 (m, 4H), 1.27-1.38 (m, 28H), 0.87 (t, 6H)

[0127] Example 12 12-1. The compound of formula (L) below was produced according to the synthesis scheme shown in FIG. [ka]

[0128] 12-2. Synthesis of Compound of Formula (L) 2-Butyloctyl 6-acrylamidohexanoate (850.65 mg, 2.43 mmol, 2.60 eq) synthesized in Example 4-2, tert-butyl N-(2-aminoethyl)carbamate (150.00 mg, 0.94 mmol, 1.00 eq), and n-BuOH (10 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to obtain impure 2-butyloctyl 8-(3-((6-((2-butyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate. The compound of formula (L) was then synthesized without further purification. 2-Butyloctyl 8-(3-((6-((2-butyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate (143.20 mg, 0.16 mmol) and methylene chloride (2 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.2 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to obtain the compound of formula (L) (85.1 mg, 67%). 1 H-NMR (400 MHz, CDCl3) δ 6.38 (t, 2H), 3.96 (d, 4H), 3.18 (q, 4H), 2.93 (t, 2H), 2.67 (t, 4H), 2.58 (t, 2H), 2.29-2.36 (m, 8H), 1.61-1.66 (m, 6H), 1.48-1.60 (m, 4H), 1.27-1.38 (m, 38H), 0.90-0.92 (m, 12H)

[0129] Example 13 13-1. The compound of formula (M) below was produced according to the synthesis scheme shown in FIG. [ka]

[0130] 13-2. Synthesis of Compound of Formula (M) To a 100 mL three-neck RBF, 2-hexyloctyl 6-acrylamidohexanoate (1429.07 mg, 3.74 mmol, 2.40 eq) synthesized in Example 5-2, tert-butyl N-(2-aminoethyl)carbamate (250.00 mg, 1.56 mmol, 1.00 eq), and n-BuOH (10 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-hexyloctyl 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of the compound of formula (M) without further purification steps. 2-Hexyloctyl 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (3 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.3 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (8:1:0.1) to give the compound of formula (M) (116.6 mg, 9.1% yield for two steps).

[0131] 1H-NMR (400 MHz, CDCl3) δ 6.94 (t, 2H), 3.96 (d, 4H), 3.12-3.20 (m, 6H), 2.73 (t, 2H), 2.62 (t, 4H), 2.29-2.37 (m, 8H), 1.59-1.65 (m, 6H), 1.47-1.52 (m, 4H), 1.20-1.39 (m, 46H), 0.90 (t, 12H)

[0132] Example 14 14-1. The compound of formula (N) below was produced according to the synthesis scheme shown in FIG. [ka]

[0133] 14-2. Synthesis of Compound of Formula (N) To a 100 mL three-neck RBF, 2-octyldodecyl 6-acrylamidohexanoate (1200.00 mg, 2.58 mmol, 2.40 eq) synthesized in Example 7-2, tert-butyl N-(2-aminoethyl)carbamate (171.99 mg, 1.07 mmol, 1.00 eq), and n-BuOH (10 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-octyldodecyl 2,2-dimethyl-8-(3-((6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of compound of formula (N) without further purification. 2-Octyldodecyl 2,2-dimethyl-8-(3-((6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (10 mL) were added to a 100 mL single-neck RBF, and trifluoroacetic acid (1.0 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to give compound of formula (N) (137.8 mg, 12.9% yield for two steps).

[0134] 1 H-NMR (400 MHz, CDCl3) δ 6.86 (t, 2H), 3.96 (d, 4H), 3.17 (q, 4H), 2.98 (t, 2H), 2.61-2.67 (m, 6H), 2.29-2.37 (m, 8H), 1.60-1.66 (m, 7H), 1.20-1.38 (m, 72H), 0.90-0.95 (m, 12H)

[0135] Example 15 15-1. The compound of formula (O) below was produced according to the synthesis scheme shown in FIG. [ka]

[0136] 15-2. Synthesis of Compound of Formula (O) To a 100 mL three-necked RBF, 2-hexyloctyl 8-acrylamidooctanoate (1130.14 mg, 2.76 mmol, 2.60 eq) synthesized in Example 8-2, tert-butyl N-(2-aminoethyl)carbamate (170.00 mg, 1.06 mmol, 1.00 eq), and n-BuOH (11 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give impure 2-hexyloctyl 8-(3-((8-((2-hexyloctyl)oxy)-8-oxooctyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaicosan-20-oate, which was then used for the synthesis of compound of formula (O) without further purification steps. 2-Hexyloctyl 8-(3-((8-((2-hexyloctyl)oxy)-8-oxooctyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaicosan-20-oate and methylene chloride (4.4 mL) were added to a 25 mL single-neck RBF, and trifluoroacetic acid (0.4 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give the compound of formula (O) (225.5 mg, 24.2% yield for two steps).

[0137] 1H-NMR (400 MHz, CDCl3) δ 6.81 (t, 2H), 3.96 (d, 4H), 3.15 (q, 4H), 3.03 (t, 2H), 2.63-2.66 (m, 6H), 2.35 (t, 4H), 2.29 (t, 4H), 1.59-1.62 (m, 6H), 1.46-1.50 (m, 4H), 1.27-1.39 (s, 55H), 0.87-0.92 (m, 12H)

[0138] Example 16 16-1. The compound of formula (P) below was produced according to the synthesis scheme shown in FIG. [ka]

[0139] 16-2. Synthesis of Compound of Formula (P) To a 100 mL three-neck RBF, 2-decyltetradecyl 6-acrylamidohexanoate (891.15 mg, 1.71 mmol, 2.40 eq) synthesized in Example 9-2, tert-butyl N-(2-aminoethyl)carbamate (114.00 mg, 0.71 mmol, 1.00 eq), and n-BuOH (6.2 mL) were added, and the mixture was stirred and refluxed. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (20:1:0.1) to give impure 2-decyltetradecyl 8-(3-((6-((2-decyltetradecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate, which was then used for the synthesis of compound (P) without further purification. To a 25 mL single-neck RBF was added 2-decyltetradecyl 8-(3-((6-((2-decyltetradecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-oate and methylene chloride (6.0 mL), and trifluoroacetic acid (0.6 mL) was added dropwise. After stirring at room temperature for 24 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to give compound of formula (P) (157.9 mg, 20.1% yield for two steps).

[0140] 1 H-NMR (400 MHz, CDCl3) δ 6.98 (t, 2H), 3.96 (d, 4H), 3,16 (q, 4H), 3.01 (t, 2H), 2.65 (t, 6H), 2.36 (t, 4H), 2.30 (t, 4H), 1.60-1.66 (m, 7H), 1.48-1.54 (m, 5H), 1.20-1.40 (m, 83H), 0.90-0.95 (m, 12H)

[0141] Example 17 17-1. The compound of formula (Q) below was produced according to the synthesis scheme shown in FIG. [ka]

[0142] 17-2. Synthesis of Compound of Formula (Q) Nonyl 6-acrylamidohexanoate (3000.00 mg, 9.63 mmol, 2.60 eq) synthesized in Example 11-2, N,N-dimethylpropanediamine (378.53 mg, 1.00 mmol, 1.00 eq), and N-BuOH (18 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (7:1:0.1) to obtain the compound of formula (Q) (1257.6 mg, yield: 47%).

[0143] 1 H-NMR (400 MHz, CDCl3) δ 4.05 (t, 4H), 3.22 (q, 4H), 2.73 (t, 4H), 2.50 (t, 2H), 2.25-2.47 (m, 10H), 2.23 (s, 6H), 1.60-1.67 (m, 10H), 1.48-1.58 (m, 4H), 1.27-1.38 (m, 28H), 0.88 (t, 6H)

[0144] Example 18 18-1. The compound of the following formula (R) was produced according to the synthesis scheme shown in FIG. [ka]

[0145] 18-2. Synthesis of compounds of formula (R) 2-Hexyldecyl 6-acrylamidohexanoate (1500.00 mg, 3.67 mmol, 2.60 eq) synthesized in Example 2-2, N,N-dimethylpropanediamine (143.90 mg, 1.41 mmol, 1.00 eq), and N-BuOH (7 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain the compound of formula (R) (476.10 mg, yield: 37%).

[0146] 1 H-NMR (400 MHz, CDCl3) δ 6.88 (t, 2H), 3.97 (d, 4H), 3.21 (q, 4H), 2.72 (t, 4H), 2.49 (t, 2H), 2.29-2.35 (m, 10H), 2.22 (s, 6H), 1.61-1.67 (m, 9H), 1.49-1.55 (m, 4H), 1.27-1.40 (m, 50H), 0.88 (t, 12H)

[0147] Example 19 19-1. The compound of formula (S) below was produced according to the synthesis scheme shown in FIG. [ka]

[0148] 19-2. Synthesis of Compound of Formula (S) 2-Hexyldecyl 6-acrylamidohexanoate (2000.00 mg, 4.88 mmol, 3.00 eq) synthesized in Example 2-2, 2-morpholinoethan-1-ol (210.00 mg, 1.63 mmol, 1.00 eq), and n-BuOH (20 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 48 hours, the mixture was concentrated under vacuum at 80°C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (15:1:0.1) to obtain the compound of formula (S) (596.00 mg, yield: 39%).

[0149] 1 H-NMR (400 MHz, CDCl3) δ 6.82 (t, 2H), 3.96 (d, 4H), 3.69 (t, 4H), 3.22 (q, 4H), 2.76 (t, 3H), 2.58 (t, 2H), 2.43-2.49 (m, 6H), 2.29-2.34 (m, 7H), 1.61-1.67 (m, 6H), 1.38-1.54 (m, 4H), 1.27-1.38 (m, 52H), 0.88 (t, 12H)

[0150] Example 20 20-1. The compound of formula (T) below was produced according to the synthesis scheme shown in FIG. [ka]

[0151] Synthesis of 20-2.dec-3-yn-1-yl 6-acrylamidohexanoate A 500 mL three-neck RBF was charged with 6-aminohexanoic acid (3.06 g, 23.34 mmol, 1.20 eq), dec-3-yn-1-ol (3.00 g, 19.45 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (5.55 g, 29.17 mmol, 1.50 eq), and cyclohexane (130 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and aqueous NaOH. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure dec-3-yn-1-yl 6-aminohexanoate. Without further purification, the previously obtained dec-3-yn-1-yl 6-aminohexanoate, methylene chloride (130 mL), and triethylamine (4.33 g, 42.79 mmol, 2.20 eq) were added to a 500 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (1.94 g, 21.39 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to give dec-3-yn-1-yl 6-acrylamidohexanoate (765.60 mg, 12% yield).

[0152] 1 H-NMR (400 MHz, CDCl3) δ 6.29 (d, 1H), 6.11 (m, 1H), 5.64 (d, 2H), 4.15 (t, 2H), 3.36 (t, 2H), 2.49 (m, 2H), 2.35 (t, 2H), 2.15 (t, 2H), 1.67 - 1.26 (m, 14H), 0.88 (t, 3H)

[0153] 20-3. Synthesis of Compound of Formula (T) To a 100 mL three-necked RBF, dec-3-yn-1-yl 6-acrylamidohexanoate (300.00 mg, 0.94 mmol, 2.20 eq), N,N'-dimethyl-1,3-propanediamine (43.80 mg, 0.43 mmol, 1.00 eq), and n-BuOH (5 mL) were added and stirred under reflux. After 24 hours, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to obtain compound (T) (165.3 mg, 52% yield).

[0154] 1 H-NMR (400 MHz, CDCl3) δ 7.90 (s, 2H), 4.13 (t, 4H), 3.22 (q, 4H), 2.62 (t, 4H), 2.48 (m, 4H), 2.42 (m, 4H), 2.36 (t, 4H), 2.32 (t, 4H), 2.25 (s, 6H), 2.15 (m, 4H), 1.63-1.79 (m, 7H), 1.40-1.60 (m, 9H), 1.25-1.38 (m, 8H), 0.90 (t, 6H)

[0155] Example 21 21-1. The compound of formula (U) below was produced according to the synthesis scheme shown in FIG. [ka]

[0156] 21-2. Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate A 100 mL three-neck RBF was charged with 6-aminohexanoic acid (295.37 mg, 2.25 mmol, 1.20 eq), (9Z,12Z)-octadeca-9,12-dien-1-ol (500.00 mg, 1.88 mmol, 1.00 eq), p-toluenesulfonic acid monohydrate (642.47 mg, 3.38 mmol, 1.80 eq), and cyclohexane (20 mL). A Dean-Stark trap and condenser were attached and the mixture was stirred and refluxed. After 24 h, the mixture was cooled to room temperature, concentrated in vacuo, and extracted with methylene chloride and aqueous NaOH. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give impure (9Z,12Z)-octadeca-9,12-dien-1-yl 6-aminohexanoate. Without further purification, the previously obtained (9Z,12Z)-octadeca-9,12-dien-1-yl 6-aminohexanoate, methylene chloride (20 mL), and triethylamine (417.72 mg, 4.13 mmol, 2.20 eq) were added to a 100 mL three-neck RBF and cooled to 0 °C. After this, acryloyl chloride (186.82 mg, 2.06 mmol, 1.10 eq) was added dropwise. The reactor temperature was raised to room temperature (20-25 °C) and stirred. After 18 h, the mixture in the reactor was extracted with aqueous HCl, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified on a silica column using EtOAc:hexane (1:2) to obtain (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate (579.9 g, 71% yield).

[0157] 1 H NMR (400 MHz, CDCl3) δ 6.27 (dd, 1H), 6.05-6.11 (m, 1H), 5.62-5.64 (m, 2H), 5.34-5.38 (m, 4H), 4.05 (t, 2H), 3.33 (q, 2H), 2.76 (t, 2H), 2.29 (t, 2H), 2.05 (q, 4H), 1.56-1.67 (m, 6H), 1.28-1.39 (m, 18H), 0.89 (t, 3H)

[0158] 21-3. Synthesis of Compounds of Formula (U) (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate (305.258 mg, 0.70 mmol, 2.40 eq), N,N'-dimethyl-1,3-propanediamine (30.00 mg, 0.29 mmol, 1.00 eq), and n-BuOH (3 mL) were added to a 100 mL three-neck RBF and refluxed with stirring. After 24 h, the mixture was concentrated under vacuum at 80 °C and purified on a silica column using methylene chloride:methanol:ammonium hydroxide (10:1:0.1) to give compound (U) (185.10 mg, 65% yield).

[0159] 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H), 5.34-5.38 (m, 8H), 4.05 (s, 4H), 3.22 (q, 4H), 2.80 (t, 4H), 2.60 (t, 4H), 2.42 (t, 4H), 2.36 (t, 4H), 2.28 (t, 4H), 2.03 (s, 6H), 2.05 (q, 8H), 1.60-1.68 (m, 10H), 1.49-1.60 (m, 4H), 1.27-1.37 (m, 36H), 0.89 (t, 3H)

[0160] Example 22 22-1. The compound of formula (V) below was produced according to the synthesis scheme shown in FIG. [ka]

[0161] Synthesis of 22-2,1-cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate 1-Cyclopropylnonan-1-ol (8.68 g, 47.1 mmol, 1.00 eq) and methylene chloride (170 mL) were added to a 500 mL three-neck RBF at 25 °C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (11.7 g, 61.3 mmol, 1.30 eq) and triethylamine (EtN) (9.54 g, 94.2 mmol, 2.00 eq) were added to the mixture. 6-(((benzyloxy)carbonyl)amino)hexanoic acid (15.0 g, 56.5 mmol, 1.20 eq) and 4-dimethylaminopyridine (DMAP) (1.15 g, 9.42 mmol, 0.20 eq) were added. The mixture was purged with nitrogen (N) three times. The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with 600 mL of methylene chloride (200 mL x 3). The methylene chloride layer was collected, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether (PE) / ethyl acetate (EtOAc) = 10 / 1 to 1 / 100). 1-Cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate (9.00 g, 20.9 mmol, 44.3% yield) was obtained as a colorless oil.

[0162] 1 H NMR (400 MHz, CDCl3) δ 4.27 (td, 1H), 3.41 (t, 2H), 2.31 (t, 2H), 1.89 - 1.74 (m, 2H), 1.68 - 1.60 (m, 4H), 1.43 (s, 2H), 1.38 - 1.25 (m, 16H), 0.99 - 0.92 (m, 1H), 0.89 (t, 3H), 0.59 - 0.51 (m, 1H), 0.49 - 0.42 (m, 1H), 0.38 (qd, 1H), 0.31 - 0.21 (m, 1H)

[0163] Synthesis of 22-3.1-cyclopropylnonyl 6-aminohexanoate Under an argon (Ar) atmosphere, palladium catalyst (Pd / C) (2.22 g, 2.09 mmol, 10% purity, 0.10 eq) was added to a 35 mL portion of a cylindrical flask. Tetrahydrofuran (THF) (90 mL) was added to the upper portion of the cylindrical flask. 1-Cyclopropylnonyl 6-(((benzoyloxy)carbonyl)amino)hexanoate (9.00 g, 20.9 mmol, 1.00 eq) was added to the mixture. Hydrogen (H) was charged to 50 psi. The mixture was stirred at 50 °C for 16 h. The Pd / C filter cake was safely filtered and collected. The filtrate was concentrated under pressure to give a residue. The residue was purified by column chromatography (SiO2, methylene chloride / methanol = 10 / 1 to 1 / 100) to obtain 1-cyclopropylnonyl 6-aminohexanoate (6.00 g, 20.2 mmol, yield 96.7%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.27 (td, 1H), 2.71 (t, 2H), 2.32 (t, 2H), 1.71 - 1.60 (m, 5H), 1.53 - 1.43 (m, 2H), 1.42 - 1.18 (m, 15H), 1.00 - 0.92 (m, 1H), 0.89 (t, 3H), 0.59 - 0.50 (m, 1H), 0.49 - 0.42 (m, 1H), 0.38 (qd, 1H), 0.33 - 0.18 (m, 1H)

[0164] Synthesis of 22-4,1-cyclopropylnonyl 6-acrylamidohexanoate To a 100 mL three-neck RBF, methylene chloride (30 mL) and 1-cyclopropylnonyl 6-aminohexanoate (3.00 g, 10.1 mmol, 1.00 eq) were added. Triethylamine (TEA) (4.59 g, 45.4 mmol, 4.50 eq) was added to the mixture at 0 °C. Acryloyl chloride (1.37 g, 15.1 mmol, 1.50 eq) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h and then gradually cooled to room temperature. The reaction mixture was neutralized with water (40 mL) at 20 °C and extracted with methylene chloride (50 mL x 3). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 1 / 100). 1-Cyclopropylnonyl 6-acrylamidohexanoate (2.60 g, 7.40 mmol, 73.3% yield) was obtained as a yellow oil.

[0165] 1 H NMR (400 MHz, CDCl3) δ6.34 - 6.21 (m, 1H), 6.15 - 5.98 (m, 1H), 5.64 (br dd, 1H), 4.27 (td, 1H), 3.41 - 3.08 (m, 2H), 2.40 - 2.22 (m, 2H), 1.72 - 1.61 (m, 4H), 1.58 (s, 6H), 1.45 - 1.35 (m, 2H), 1.27 (br s, 9H), 1.00 - 0.91 (m, 1H), 0.89 (t, 3H), 0.61 - 0.51 (m, 1H), 0.50 - 0.41 (m, 1H), 0.37 (qd, 1H), 0.30 - 0.20 (m, 1H)

[0166] 22-5. Synthesis of Compound of Formula (V) A 50 mL three-neck RBF was charged with a mixture of dimethyl sulfoxide (DMSO) (3.5 mL) and water (3.5 mL) and 1-cyclopropylnonyl 6-acrylamidohexanoate (0.70 g, 1.99 mmol, 1.00 eq). To the mixture was added TEA (134 mg, 1.33 mmol, 0.67 eq). To the mixture was added N1,N3-dimethylpropane-1,3-diamine (67.8 mg, 663 μmol, 0.33 eq). The mixture was purged with N2 three times. The mixture was stirred at 100 °C for 48 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, methylene chloride / methanol = 10 / 1) to give 0.3 g of compound of formula (V) with relatively low purity. This was purified by reverse-phase HPLC (column: Phenomenexluna C18 15025 mm 10 μm; mobile phase: [water (FA)-ACN]; gradient: 40%-70% B, 10 min) to give the compound of formula (V) (0.15 g, 186 μmol, yield 28.1%, purity 96.1%) as a yellow oil.

[0167] 1 H NMR (400 MHz, CDCl3) δ7.91 (br s, 2H), 4.26 (td, 2H), 3.31 - 3.17 (m, 4H), 2.61 (t, 4H), 2.41 (t, 4H), 2.38 - 2.33 (m, 4H), 2.33 - 2.27 (m, 4H), 2.25 (s, 6H), 1.72 - 1.62 (m, 10H), 1.56 - 1.48 (m, 4H), 1.41 - 1.25 (m, 28H), 1.01 - 0.92 (m, 2H), 0.89 (t, 6H), 0.59 - 0.50 (m, 2H), 0.49 - 0.41 (m, 2H), 0.36 (qd, 2H), 0.31 - 0.21 (m, 2H)

[0168] [Production Example of Drug Delivery Composition] 1. Preparation of Raw Materials According to the table below, the materials required for the preparation of the formulation were dissolved in each dilution solvent to prepare the required concentration. During dissolution, the materials were kept at room temperature, and then the solvent was added to dissolve them.

[0169] [Table 3]

[0170] 2.Mixing of raw materials The N-P ratio (amine group of lipid:phosphate group of mRNA) was 10, and the ratio of each compound of formulas (A-V):DMG-PEG:DSPC:cholesterol was 50:1.5:10:38.5. Ethanol was added to the ethanol layer so that the total molecular weight of all raw materials was within 12.5 mM, and the aqueous and ethanol phases were mixed while maintaining a volume ratio of 3:1. After mixing, buffer exchange was performed to reduce the total ethanol content as follows: The mixture was concentrated by centrifugation at 4,000 rpm to one-third of its original volume using an Amicon-Ultra tube filter (Merk Millipore, UFC505096 or UFC805024, pore size: 50K, volume: 0.5 mL or 4 mL). It was then diluted with three volumes of PBS and concentrated by centrifugation. This process was repeated six times to perform buffer exchange.

[0171] More specifically, the steps are as follows: 1) Two autoclaved tubes were prepared (tubes (A) and (B)). 2) Each compound of formulae (A to U), DSPC, c-cholesterol, and DMG-PEG were added to tube (A) in the molar amounts calculated according to the experimental conditions, and mixed using a brutex mixer. 3) In the ethanol phase, ethanol was added as necessary so that the total molecular weight of all raw materials was within 12.5 mM. 4) In tube (B), mRNA was mixed with 20 mM sodium acetate buffer (pH 4.6) (prepared by diluting the mRNA to 20 mM with 3 M sodium acetate buffer and titrating it to pH 4.6 with 1 M hydrochloric acid). The aqueous phase was added so that the total volume was three times the ethanol phase. 5) Tube (A) and tube (B) were mixed using a microfluidics device (Ignite, Precision Nanosystems). The microfluidics operating conditions were FRR (flow ratio) C:R = 3:1, TRR (total flow rate) 12 mL / min. 6) The mixture obtained in step 5) was centrifuged at 4,000 rpm using an Amicon-Ultra tube filter (50K) to a 1 / 3 level, then diluted 3 times with PBS and concentrated by centrifugation. This process was repeated 6 times to concentrate to the desired volume.

[0172] 3. Evaluation of the physical properties of the formulation 1) The particle characteristics (i.e., zeta-average particle size (Z-average), polydispersity index (PDI), and zeta potential) of the manufactured formulations were determined using a particle size analyzer (dynamic light scattering, DLS), and the results are shown in Table 1 below. 2) The mRNA encapsulation efficiency of the produced preparation was confirmed by RiboGreen assay, and the results are shown in Table 1 below.

[0173] [Table 4]

Claims

1. A lipid having a structure selected from the following or its ionized form: 【Chemistry 1】 wherein in said structure, at least two of the R groups are R and the remaining R groups are R; wherein each Rx is independently 【Chemistry 2】 is selected from where a, b, and c are each independently an integer from 2 to 20; 1 is a substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, 【Transformation 3】 represents a substituted or unsubstituted methylene group, each R is independently H or a substituted or unsubstituted alkyl group, and two R groups that are not H may be linked together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently a substituted or unsubstituted alkylene group, and may optionally have an ether bond (—O—), a thioether bond (—S—), or a disulfide bond (—S—S—) in its structure.

2. Each Rx is independently 【Chemistry 4】 is selected from where a, b, and c are each independently an integer from 2 to 20; 1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 is a hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent C 2-24 is a hydrocarbon group, 【Transformation 5】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-20 alkyl groups, wherein the alkyl groups are independently unsubstituted or —OH, C 1-20 Alkyl, C 1-20 Alkoxy, —NH 2 , —NH(C 1-20 alkyl), -N(C 1-20 alkyl) 2 , optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20 two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently C 1-20 alkylene groups, each independently unsubstituted or —OH, C 1-20 Alkyl, C 1-20 Alkoxy, —NH 2 , —NH(C 1-20 alkyl), -N(C 1-20 alkyl) 2 , optionally substituted C 3-20 Carbocyclic groups and optionally substituted C 3-20 The lipid of claim 1 , substituted with one or more heterocyclic groups.

3. Each Rx is independently 【Transformation 6】 is selected from where a, b, and c are each independently an integer from 2 to 15; 1 is a substituted or unsubstituted, saturated or unsaturated divalent C 1-12 is a hydrocarbon group, R 2 is a substituted or unsubstituted unsaturated monovalent C 2-24 is a hydrocarbon group, 【Transformation 7】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-10 alkyl groups, wherein the alkyl groups are independently unsubstituted or selected from the group consisting of —OH, C 1-10 Alkyl, C 1-10 Alkoxy, —NH 2 , —NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently C 1-10 alkylene groups, each independently unsubstituted or —OH, C 1-10 Alkyl, C 1-10 Alkoxy, —NH 2 , —NH(C 1-10 alkyl), -N(C 1-10 alkyl) 2 , optionally substituted C 3-10 Carbocyclic groups and optionally substituted C 3-10 The lipid of claim 2 , substituted with one or more heterocyclic groups.

4. Each Rx is independently 【Transformation 8】 wherein a, b, and c are each independently an integer from 3 to 12; 1 is a substituted or unsubstituted C 1-12 Alkylene group, substituted or unsubstituted C 2-12 Alkenylene group or substituted or unsubstituted C 2-12 is an alkynylene group, and R 2 is a substituted or unsubstituted C 2-24 Alkenyl group or substituted or unsubstituted C 2-24 is an alkynyl group, 【Chemistry 9】 represents a substituted or unsubstituted methylene group, Each R is independently H or C 1-6 alkyl groups, wherein the alkyl groups are independently unsubstituted or selected from the group consisting of -OH and -NH 2 and two R groups that are not H may be joined together with the nitrogen atom to which they are attached to form a ring structure; Each L is independently an unsubstituted C 1-6 The lipid of claim 3, which is an alkylene group.

5. 5. The lipid of claim 4, wherein the lipid has a structure selected from the following formulas A to V: Table 1-1 Table 1-2 Table 1-3

6. The following steps: (1) reacting a compound of formula (a) with a compound of formula (b) to obtain a compound of formula (c); (2) reacting a compound of formula (c) with a compound of formula (d) to obtain a compound of formula (e); and (3) reacting the compound of formula (e) with the compound of formula (f) and deprotecting the reaction product A method for producing a lipid having a structure represented by formula (1-1), comprising: The formula (a) is H 2 N-(CH 2 ) a -C(=O)OH, The formula (b) is OH—R′, The formula (c) is H 2 N-(CH 2 ) a -C(=O)O-R', The formula (d) is 【Chemistry 10】 and The formula (e) is H 2 C=CH-C(=O)-HN-(CH 2 ) a -C(=O)O-R', The formula (f) is H 2 N-(CH 2 ) 1-20 -NH-C(=O)OC(CH 3 ) 3 and The formula (1-1) is H 2 N-(CH 2 ) 1-20 -N[-CH 2 -CH 2 -C(=O)-HN-(CH 2 ) a -C(=O)OR'] 2 The manufacturing method as described above. (In the formula, each R' is independently 【Chemistry 11】 where * represents the point of attachment to the adjacent oxygen atom; 【Chemistry 12】 represents a substituted or unsubstituted methylene group, a, b, and c are each independently an integer from 2 to 20; X is selected from the group consisting of F, Cl, Br and I.

7. A method for producing a lipid having a structure represented by formula (1-2), comprising a step of reacting the compound of formula (e) obtained in claim 6 with a compound of formula (g): The formula (e) is H 2 C=CH-C(=O)-HN-(CH 2 ) a -C(=O)O-R', The formula (g) is H 2 N-(CH 2 ) 1-20 -N(C 1-20 alkyl) 2 and The formula (1-2) is (C 1-20 alkyl) 2 N-(CH 2 ) 1-20 -N[-CH 2 -CH 2 -C(=O)-HN-(CH 2 ) a -C(=O)OR'] 2 The manufacturing method as described above. (In the formula, each R' is independently 【Chemistry 13】 where * represents the point of attachment to the adjacent oxygen atom, 【Chemistry 14】 represents a substituted or unsubstituted methylene group, and a, b, and c are each independently an integer of 2 to 20.

8. A method for producing a lipid having a structure represented by formula (1-3), comprising a step of reacting the compound of formula (e) obtained in claim 6 with a compound of formula (h), The formula (e) is H 2 C=CH-C(=O)-HN-(CH 2 ) a -C(=O)O-R', The formula (h) is (C 1-10 alkyl)-NH-(CH 2 ) 1-20 -NH-(C 1-10 alkyl), The formula (1-3) is A-N(C 1-10 alkyl)-(CH 2 ) 1-20 -N(C 1-10 The above-mentioned production method, wherein A is a substituted or unsubstituted alkyl group. (In the formula, each R' is independently 【Chemistry 15】 where * represents the point of attachment to the adjacent oxygen atom; 【Chemistry 16】 represents a substituted or unsubstituted methylene group, A is -CH 2 -CH 2 -C(=O)-HN-(CH 2 ) a -C(=O)O-R', a, b, and c are each independently an integer from 2 to 20; X is selected from the group consisting of F, Cl, Br and I.

9. The following steps: (1) reacting a compound of formula (a) with a compound of formula (b') to obtain a compound of formula (c'); (2) reacting a compound of formula (c') with a compound of formula (d) to obtain a compound of formula (e'); and (3) reacting the compound of formula (e') with the compound of formula (h) A method for producing a lipid having a structure represented by formula (1-4), comprising: The formula (a) is H 2 N-(CH 2 ) a -C(=O)OH, The formula (b') is OH-R 2 and The formula (c') is H 2 N-R 1 -C(=O)O-R 2 and The formula (d) is 【Chemistry 17】 and The formula (e') is H 2 C=CH-C(=O)-HN-R 1 -C(=O)O-R 2 and The formula (h) is (C 1-10 alkyl)-NH-(CH 2 ) 1-20 -NH-(C 1-10 alkyl), The formula (1-4) is A'-N(C 1-10 alkyl)-(CH 2 ) 1-20 -N(C 1-10 The above-mentioned production method, wherein A' is a substituted or unsubstituted alkyl group. (Wherein A' is -CH 2 -CH 2 -C(=O)-HN-R 1 -C(=O)O-R 2 and R 1 are independently substituted or unsubstituted, saturated or unsaturated divalent hydrocarbon groups, R 2 are independently a substituted or unsubstituted unsaturated monovalent hydrocarbon group, a is an integer from 2 to 20, and X is selected from the group consisting of F, Cl, Br, and I.

10. A drug delivery composition comprising the lipid according to any one of claims 1 to 5.

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