Cationic lipid and method for producing same

Abstract

The present invention relates to a cationic lipid and a method for producing the same, and more specifically to a cationic lipid that easily forms a complex with an anionic drug and is useful for drug delivery, and a method for producing the same.

Description

[Technical Field]

[0001] The present invention relates to a cationic lipid and a method for producing the same, and more specifically to a cationic lipid that easily forms a complex with an anionic drug and is useful for drug delivery, and a method for producing 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 challenges to commercialization due to risks such as non-specific immune responses and complex manufacturing processes. Therefore, recent research has focused on the use of non-viral delivery vehicles, and research is being conducted toward improving these drawbacks. 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, conventional cationic lipids used in ionic lipid nanoparticles, which consist of cationic lipids, neutral lipids, and fusogenic lipids, have drawbacks such as complex synthesis methods, cytotoxicity, and low intracellular nucleic acid delivery efficiency. [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 cationic 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 represented by the following formula (1):

[0008] [ka] (In the formula, M1 and M2 each independently represent a divalent linker group, R1 and R2 are each independently a substituted or unsubstituted carbocyclic or heterocyclic group; R3 is a hydrogen atom or a substituted or unsubstituted organic group optionally containing one or more heteroatoms; R4~R 11 are each independently a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon group, Me is a methyl group, a, b, c, and d are each independently an integer of 1 to 20.

[0009] According to one embodiment of the present invention, in the formula (1), M1 and M2 each independently represent -C(O)O-, -OC(O)-, -OC(O)-M'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)-, -SS-, arylene (more specifically, C 6-20 arylene), and heteroarylene (more specifically, C having one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S). 3-20 heteroarylene), where M' is a direct bond, C 1-13 Alkylene or C 2-13 alkenylene, and each R' is independently a hydrogen atom, C 1-18 Alkyl and C 2-18 It may be selected from the group consisting of alkenyl.

[0010] According to one embodiment of the present invention, in the formula (1), R and R are each independently substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 3-20 Cycloalkenyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 3-20 Heterocycloalkyl, substituted or unsubstituted C 3-20 Heterocycloalkenyl, and substituted or unsubstituted C 3-20and heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0011] According to one embodiment of the present invention, in the formula (1), R3 is a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclic group, -(CH2) n Q, -(CH2) n and -CQ(R)2, wherein each R is independently selected from the group consisting of a hydrogen atom, C 1-3 Alkyl and C 2-3 alkenyl; Q may be selected from the group consisting of a carbocyclic group, a heterocyclic group, -OR, -O(CH) n N(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R 12 , N(R)S(O)2R 12 , -O(CH2) n OR, -N(R)C(=NR 13 )N(R)2, -N(R)C(=CHR 13 )N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, -N(OR)C(=NR 13 )N(R)2, -N(OR)C(=CHR 13 )N(R)2, -C(=NR 13 )N(R)2, -C(=NR 13 )R, —C(O)N(R)OR and —C(R)N(R)C(O)OR, where each n is independently an integer from 1 to 5; R 12 is C 3-6 is selected from the group consisting of carbocyclic and heterocyclic groups; R13 are H, CN, NO2, C 1-6 Alkyl, -OR, -S(O)2R, -S(O)2N(R)2, C 2-6 Alkenyl, C 3-6 and each R is independently selected from the group consisting of a hydrogen atom, a C 1-3 Alkyl and C 2-3 alkenyl, and each X is independently selected from the group consisting of F, CI, BR, and I, with the proviso that R3 is -(CH2) n Q, -(CH2) n When CHQR, -CHQR, or -CQ(R), (i) when n is 1, 2, 3, 4, or 5, Q is not -N(R), or (ii) when n is 1 or 2, Q is not a 5-, 6-, or 7-membered heterocycloalkyl.

[0012] According to one embodiment of the present invention, in the formula (1), R4 to R 11 are each independently a hydrogen atom, C 1-3 Alkyl and C 2-3 It may be selected from the group consisting of alkenyl.

[0013] According to one embodiment of the present invention, in the formula (1), a, b, c and d may each independently be an integer of 1-15.

[0014] More specifically, in the formula (1), M1 and M2 may each independently be selected from the group consisting of -C(O)O-, -OC(O)-, -OC(O)-M'-C(O)O-, -C(O)N(R')-, -N(R')C(O)- and -C(O)- (wherein M' and R' are as defined above).

[0015] More specifically, in the formula (1), R1 and R2 are each independently a substituted or unsubstituted C 3-20 Cycloalkyl and substituted or unsubstituted C 3-20heterocycloalkyl, wherein said heterocycloalkyl may have one or more (eg, 1 to 3) heteroatoms selected from N, O, and S.

[0016] More specifically, in the formula (1), R3 is a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Carbocyclic groups (e.g., C 3-6 cycloalkyl).

[0017] More specifically, in the formula (1), R4 to R 11 are each independently a hydrogen atom or C 1-3 It may also be alkyl.

[0018] More specifically, in the formula (1), a, b, c, and d may each independently be an integer of 3 to 11.

[0019] More specifically, in the formula (1), M1 and M2 may each independently be -C(O)O- or -OC(O)-.

[0020] More specifically, in the formula (1), R1 and R2 are each independently a substituted or unsubstituted C 3-6 It may also be cycloalkyl.

[0021] More specifically, in the formula (1), R3 is a hydrogen atom or an unsubstituted C 1-3 It may also be alkyl.

[0022] More specifically, in the formula (1), R4 to R 11 may be a hydrogen atom.

[0023] More specifically, in the formula (1), a, b, c and d may each independently be an integer of 5 to 9.

[0024] More specifically, the lipid may have a structure selected from the following formulas (A to O).

[0025] [ka] [ka]

[0026] A second aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1'), the method 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).

[0027] [ka] (In the formula, M1, R1, R3, R4, R5, R8, R9, Me, a, and b are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.)

[0028] A third aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1), the method 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') and a compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (f).

[0029] [ka] (In the formula, M1, M2, R1~R 11, Me, a, b, c, and d are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.

[0030] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1'), comprising the steps of: (1) reacting a compound of formula (i) with a compound of formula (ii) to obtain a compound of formula (iii); (2) reacting a compound of formula (iii) with a compound of formula (iv) to obtain a compound of formula (v); (3) reacting a compound of formula (v) with a compound of formula (vi) to obtain a compound of formula (vii); and (4) reacting the compound of formula (v) with a compound of formula (vii).

[0031] [ka] (In the formula, M1, R1, R3, R4, R5, R8, R9, Me, a, and b are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.)

[0032] A fifth aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1), the method comprising the steps of: (1) reacting a compound of formula (i') with a compound of formula (ii') to obtain a compound of formula (iii'); (2) reacting a compound of formula (iii') with a compound of formula (iv') to obtain a compound of formula (v'); (3) reacting a compound of formula (v') with a compound of formula (vi) to obtain a compound of formula (vii'); and (4) reacting the compound of formula (vii') with the compound of formula (v) obtained in the fourth aspect of the present invention.

[0033] [ka] (In the formula, M1, M2, R1~R11 , Me, a, b, c, and d are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.

[0034] A sixth aspect of the present invention provides a drug delivery composition comprising a lipid according to the present invention. [Effects of the Invention]

[0035] The lipids having a specific structure according to the present invention can easily form a complex with an anionic drug, and by utilizing this complex, the drug can be efficiently delivered to the target biological tissue. [Brief explanation of the drawings]

[0036] [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. BEST MODE FOR CARRYING OUT THE INVENTION

[0037] The present invention will now be described in further detail.

[0038] The lipid provided by the first aspect of the present invention has a structure represented by formula (1):

[0039] [ka] (In the formula, M1 and M2 each independently represent a divalent linker group, R1 and R2 are each independently a substituted or unsubstituted carbocyclic or heterocyclic group; R3 is a hydrogen atom or a substituted or unsubstituted organic group optionally containing one or more heteroatoms; R4~R 11 are each independently a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon group, Me is a methyl group, a, b, c, and d are each independently an integer of 1 to 20.

[0040] As used herein, the term "substituted or unsubstituted" of any group means that the group is not substituted or does not contain a hydroxy group or a C group, unless otherwise specified. 1-6 It means that it is substituted with an alkyl group.

[0041] According to one embodiment of the present invention, in the formula (1), M1 and M2 each independently represent -C(O)O-, -OC(O)-, -OC(O)-M'-C(O)O-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, -P(O)(OR')O-, -S(O)-, -SS-, arylene (more specifically, C 6-20 Arylene, more specifically, C 6-10 arylene), and heteroarylene (more specifically, C having one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S). 3-20 Heteroarylene, more specifically C 3-10 heteroarylene), where M' is a direct bond, C 1-13 Alkylene (more specifically, C 1-6 alkylene) or C 2-13 Alkenylene (more specifically, C 2-6 alkenylene), and each R' may independently represent a hydrogen atom, C 1-18 Alkyl (more specifically, C 1-10 Alkyl, more specifically C 1-6 alkyl) and C 2-18 Alkenyl (more specifically, C 2-10 Alkenyl, more specifically C 2-6 alkenyl).

[0042] According to one embodiment of the present invention, in the formula (1), R and R are each independently substituted or unsubstituted C 3-20 Cycloalkyl (more specifically, C 3-10 Cycloalkyl, more specifically, C 3-6 cycloalkyl), substituted or unsubstituted C 3-20 Cycloalkenyl (more specifically, C 3-10 Cycloalkenyl, more specifically C 3-6 cycloalkenyl), substituted or unsubstituted C 6-20 Aryl (more specifically, C 6-10aryl, more specifically C aryl), substituted or unsubstituted C 3-20 Heterocycloalkyl (more specifically, C 3-10 Heterocycloalkyl, more specifically C 3-6 heterocycloalkyl), substituted or unsubstituted C 3-20 Heterocycloalkenyl (more specifically, C 3-10 Heterocycloalkenyl, more specifically C 3-6 heterocycloalkenyl), and substituted or unsubstituted C 3-2 0 heteroaryl (more specifically, C 3-10 Heteroaryl, more specifically C 3-6 and heteroaryl), wherein the heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently may have one or more (e.g., 1 to 3) heteroatoms selected from N, O, and S.

[0043] According to one embodiment of the present invention, in the formula (1), R3 is a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclic group, -(CH2) n Q, -(CH2) n -CHQR, -CHQR and -CQ(R), wherein each R is independently a hydrogen atom, C 1-3 Alkyl and C 2-3 alkenyl; Q may be selected from the group consisting of a carbocyclic group, a heterocyclic group, -OR, -O(CH) n N(R)2, -C(O)OR, -OC(O)R, -CX3, -CX2H, -CXH2, -CN, -N(R)2, -C(O)N(R)2, -N(R)C(O)R, -N(R)S(O)2R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(R)R 12 , N(R)S(O)2R 12 , -O(CH2) n OR, -N(R)C(=NR 13 )N(R)2, -N(R)C(=CHR 13)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O)2R, -N(OR)C(O)OR, -N(OR)C(O)N(R)2, -N(OR)C(S)N(R)2, -N(OR)C(=NR 13 )N(R)2, -N(OR)C(=CHR 13 )N(R)2, -C(=NR 13 )N(R)2, -C(=NR 13 )R, —C(O)N(R)OR and —C(R)N(R)C(O)OR, where each n is independently an integer from 1 to 5; R 12 is C 3-6 is selected from the group consisting of carbocyclic and heterocyclic groups; R 13 are H, CN, NO2, C 1-6 Alkyl, -OR, -S(O)2R, -S(O)2N(R)2, C 2-6 Alkenyl, C 3-6 and each R is independently selected from the group consisting of a hydrogen atom, a C 1-3 Alkyl and C 2-3 alkenyl, and each X is independently selected from the group consisting of F, CI, BR, and I, with the proviso that R3 is -(CH2) n Q, -(CH2) n When CHQR, -CHQR, or -CQ(R), (i) when n is 1, 2, 3, 4, or 5, Q is not -N(R), or (ii) when n is 1 or 2, Q is not a 5-, 6-, or 7-membered heterocycloalkyl.

[0044] According to one embodiment of the present invention, in the formula (1), R4 to R 11 are each independently a hydrogen atom, C 1-3 Alkyl and C 2-3 It may be selected from the group consisting of alkenyl.

[0045] According to one embodiment of the present invention, in the formula (1), a, b, c and d may each independently be an integer of 1-15.

[0046] More specifically, in the formula (1), M1 and M2 may each independently be -C(O)O- or -OC(O)-.

[0047] More specifically, in the formula (1), R1 and R2 are each independently a substituted or unsubstituted C 3-6 It may also be cycloalkyl.

[0048] More specifically, in the formula (1), R3 is a hydrogen atom or a substituted or unsubstituted C 1-3 alkyl, and more particularly unsubstituted C 1-3 C substituted with alkyl or hydroxy groups 1-3 It may also be alkyl.

[0049] More specifically, in the formula (1), R4 to R 11 may be a hydrogen atom.

[0050] More specifically, in the formula (1), a, b, c, and d may each independently be an integer of 3 to 11, and more specifically, an integer of 5 to 9.

[0051] More specifically, the lipid may have a structure selected from the following formulas (A to O).

[0052] [ka] [ka]

[0053] A second aspect of the present invention provides a method for producing a lipid having a structure represented by the following formula (1') which is included in the formula (1), comprising 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 the 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 a compound of formula (f).

[0054] [ka] (In the formula, M1, R1, R3, R4, R5, R8, R9, Me, a, and b are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.)

[0055] 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., tetrahydrofuran (THF)) at low to room temperature (e.g., -75°C to 30°C), the reaction in step (2) can be carried out in a solvent (e.g., methylene chloride (DCM)) in the presence of a catalyst (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), triethylamine (EtN, TEA) or a combination thereof) at room temperature (e.g., 20°C to 30°C), and the reaction in step (3) can be carried out in a solvent (e.g., ethanol (EtOH) or THF) optionally in the presence of Na2CO3 or a catalyst (e.g., N,N-diisopropylethylamine (DIEA)) at high temperature (e.g., 40 to 100°C), but is not limited thereto.

[0056] A third aspect of the present invention provides a method for producing a lipid having the structure represented by formula (1), 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') and the compound of formula (e) obtained in the second aspect of the present invention with a compound of formula (f).

[0057] [ka] (In the formula, M2, R2, R3, R6, R7, R 10 , R 11 , Me, c, and d are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.

[0058] In one embodiment of the lipid production method according to the third aspect of the present invention, the reaction in step (1) can be carried out in a solvent (e.g., tetrahydrofuran (THF)) at low to room temperature (e.g., -75°C to 30°C), the reaction in step (2) can be carried out in a solvent (e.g., methylene chloride (DCM)) in the presence of a catalyst (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), triethylamine (EtN, TEA) or a combination thereof) at room temperature (e.g., 20°C to 30°C), and the reaction in step (3) can be carried out in a solvent (e.g., ethanol (EtOH) or THF) optionally in the presence of Na2CO3 or a catalyst (e.g., N,N-diisopropylethylamine (DIEA)) at high temperature (e.g., 40 to 100°C), but is not limited thereto.

[0059] A fourth aspect of the present invention provides a method for producing a lipid having a structure represented by formula (1'), comprising the following steps: (1) reacting a compound of formula (i) with a compound of formula (ii) to obtain a compound of formula (iii); (2) reacting a compound of formula (iii) with a compound of formula (iv) to obtain a compound of formula (v); (3) reacting a compound of formula (v) with a compound of formula (vi) to obtain a compound of formula (vii); and (4) reacting a compound of formula (v) with a compound of formula (vii).

[0060] [ka] (In the formula, M1, R1, R3, R4, R5, R8, R9, Me, a, and b are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.)

[0061] In one embodiment of the lipid production method according to the fourth aspect of the present invention, the reaction in step (1) can be carried out in a solvent (e.g., tetrahydrofuran (THF)) in the presence of a catalyst (e.g., sodium hydride (NaH) or lithium diisopropylamide (LDA)) at low to elevated temperatures (e.g., -20°C to 60°C). The reaction in step (2) can be carried out in a solvent (e.g., methylene chloride (DCM)) in the presence of a catalyst (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), or a combination thereof) at room temperature (e.g., 20°C to 30°C). The reaction in step (3) can be carried out at elevated temperatures (e.g., 40 to 70°C). The reaction in step (4) can be carried out in a solvent (e.g., dioxane) optionally in the presence of Na2CO3 at elevated temperatures (e.g., 40 to 120°C). Examples of the reaction include, but are not limited to, the following:

[0062] A fifth aspect of the present invention provides a method for producing a lipid having the structure represented by formula (1), comprising the steps of: (1) reacting a compound of formula (i') with a compound of formula (ii') to obtain a compound of formula (iii'); (2) reacting a compound of formula (iii') with a compound of formula (iv') to obtain a compound of formula (v'); (3) reacting a compound of formula (v') with a compound of formula (vi) to obtain a compound of formula (vii'); and (4) reacting a compound of formula (vii') with a compound of formula (v) obtained in the fourth aspect of the present invention.

[0063] [ka] (In the formula, M1, M2, R1, R2, R4~R 11 , Me, a, b, c, and d are as defined in formula (1), and each X is independently selected from the group consisting of F, CI, BR, and I.

[0064] In one embodiment of the lipid production method according to the fifth aspect of the present invention, the reaction in step (1) can be carried out in a solvent (e.g., tetrahydrofuran (THF)) in the presence of a catalyst (e.g., sodium hydride (NaH) or lithium diisopropylamide (LDA)) at low to elevated temperatures (e.g., -20°C to 60°C). The reaction in step (2) can be carried out in a solvent (e.g., methylene chloride (DCM)) in the presence of a catalyst (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), or a combination thereof) at room temperature (e.g., 20°C to 30°C). The reaction in step (3) can be carried out at elevated temperatures (e.g., 40 to 70°C). The reaction in step (4) can be carried out in a solvent (e.g., dioxane) optionally in the presence of Na2CO3 at elevated temperatures (e.g., 40 to 120°C). Examples of the reaction include, but are not limited to, these.

[0065] The lipid having the structure represented by formula (1) of the present invention can easily form a complex with an anionic drug, and is therefore useful for drug delivery.

[0066] Therefore, according to a sixth aspect of the present invention, there is provided a drug delivery composition comprising a lipid having a structure represented by formula (1) of the present invention.

[0067] In one embodiment, the drug may be selected from a nucleic acid, a polypeptide, a virus, or a combination thereof.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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).

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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

[0079] Example 1 According to the synthesis scheme shown in FIG. 1, the compound of the following formula (A) was produced.

[0080] [ka]

[0081] (1) Synthesis of 1-cyclopropylnonan-1-ol A 2000 mL three-neck round-bottom flask (RBF) was charged with cyclopropanecarbaldehyde (35.0 g, 499 mmol, 1.00 eq) and tetrahydrofuran (THF) (700 mL) under a nitrogen atmosphere. The mixture was cooled to -65 °C, and then octyl magnesium bromide (2 M, 375 mL, 1.50 eq) was added and stirred at -65 °C for 2 h. The reaction vessel was heated to 15 °C and poured into saturated aqueous NH4Cl (500 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with ethyl acetate (EtOAc) (450 mL) (3 x 150 mL). The combined organic layers were concentrated in vacuo and purified on a silica column with petroleum ether: EtOAc = 50:1 → 0:1 to give 1-cyclopropylnonan-1-ol (87.5 g, 73.1%). 1H NMR (400 MHz, CHLOROFORM-d): δ 2.93 - 2.81 (m, 1H), 1.61 (br d, 2H), 1.52 - 1.27 (m, 12H), 0.95 - 0.86 (m, 4H), 0.60 - 0.45 (m, 2H), 0.34 - 0.19 (m, 2H)

[0082] (2) Synthesis of 1-cyclopropylnonyl 8-bromooctanoate A 1000 mL three-neck RBF was charged with 1-cyclopropylnonan-1-ol (30.0 g, 163 mmol, 1.00 eq), 8-bromooctanoic acid (72.6 g, 326 mmol, 2.00 eq), methylene chloride (DCM) (300 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (31.2 g, 163 mmol, 1.00 eq), and 4-dimethylaminopyridine (DMAP) (19.9 g, 163 mmol, 1.00 eq) and stirred at 25 °C for 16 h. The reactor mixture was concentrated in vacuo, then silica powder was added and the mixture was purified on a silica column with petroleum ether: EtOAc = 10:1 → 50:1 to give 1-cyclopropylnonyl 8-bromooctanoate (22.8 g, 36.0%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.29 (td, 1H), 3.59 - 3.31 (m, 2H), 2.32 (t, 2H), 1.94 - 1.75 (m, 2H), 1.73 - 1.60 (m, 4H), 1.49 - 1.25 (m, 18H), 1.03 - 0.93 (m, 1H), 0.90 (t, 3H), 0.61 - 0.24 (m, 4H)

[0083] (3) Synthesis of Compound of Formula (A) Methylamine hydrochloride (173 mg, 2.57 mmol, 1.00 eq), ethanol (EtOH) (30 mL), N,N-diisopropylethylamine (DIEA) (1.66 g, 12.8 mmol, 5.00 eq), and 1-cyclopropylnonyl 8-bromooctanoate (3.00 g, 7.70 mmol, 3.00 eq) were added to a 100 mL three-neck flask in that order and stirred at 80° C. for 72 hours. The reaction mixture was concentrated in vacuo, followed by addition of silica powder and purification on a silica column with petroleum ether: EtOAc = 10:1 → 1:1 to give compound of formula (A) (660 mg, 38.9%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.29 (td, 2H), 2.32 (br t, 8H), 2.22 (s, 3H), 1.74 - 1.60 (m, 8H), 1.54 - 1.42 (m, 4H), 1.39 - 1.23 (m, 36H), 1.02 - 0.87 (m, 8H), 0.61 - 0.23 (m, 8H)

[0084] Example 2 According to the synthesis scheme shown in FIG. 2, the compound of the following formula (B) was produced.

[0085] [ka]

[0086] (1) Synthesis of 1-cyclopropylheptan-1-ol A 2000 mL three-neck RBF was charged with cyclopropanecarbaldehyde (27.0 g, 385 mmol, 1.00 eq) and THF (500 mL) under a nitrogen atmosphere and cooled to -65 °C. Then, hexylmagnesium bromide (1 M, 500 mL, 1.30 eq) was slowly added. The mixture was stirred at -65 °C for 3 h, and the temperature of the reactor was slowly raised to 25 °C. The mixture was then poured into saturated aqueous NH4Cl (500 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layer was concentrated in vacuo, and the residue was purified on a silica column with petroleum ether: EtOAc = 50:1 → 10:1 to give 1-cyclopropylheptan-1-ol (46.0 g, 294 mmol, 76.4% yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 2.86 (td, 1H), 1.67 - 1.38 (m, 6H), 1.36 - 1.27 (m, 6H), 0.91 - 0.87 (m, 3H), 0.59 - 0.42 (m, 2H), 0.32 - 0.17 (m, 2H)

[0087] (2) Synthesis of 1-cyclopropylheptyl 6-bromohexanoate A 500 mL three-neck RBF was charged with 1-cyclopropylheptan-1-ol (10.0 g, 63.9 mmol, 1.00 eq), 6-bromohexanoic acid (12.5 g, 63.9 mmol, 1.00 eq), DCM (100 mL), EDCI (15.9 g, 83.2 mmol, 1.30 eq), and DMAP (10.2 g, 83.2 mmol, 1.30 eq) and stirred for 16 h at 25 °C. The reactor mixture was concentrated in vacuo and then purified on a silica column with petroleum ether: EtOAc = 50:1 → 10:1 to give 1-cyclopropylheptyl 6-bromohexanoate (7.50 g, 22.5 mmol, 35.1%). 1H NMR: (400 MHz, CHLOROFORM-d): δ 4.28 (td, 1H), 3.55 (t, 1H), 3.42 (t, 1H), 2.39 - 2.26 (m, 2H), 1.97 - 1.76 (m, 2H), 1.71 - 1.60 (m, 4H), 1.57 - 1.42 (m, 3H), 1.33 - 1.28 (m, 6H), 0.91 - 0.86 (m, 5H), 0.63 - 0.51 (m, 1H), 0.50 - 0.41 (m, 1H), 0.40 - 0.32 (m, 1H), 0.30 - 0.22 (m, 1H)

[0088] (3) Synthesis of the compound of formula (B) 1-Cyclopropylheptyl 6-bromohexanoate (500 mg, 1.00 eq) was added to a 100 mL three-neck RBF, and methylamine (2 M, 2 g, 42.8 eq) in THF was added under a nitrogen atmosphere, followed by stirring at 50 °C for 16 h. After stirring, the reaction mixture was added with aqueous sodium carbonate (NaCO) solution (20 mL) and stirred for 2 h to adjust the pH to 8. The mixture was then extracted with DCM (30 mL x 3), and the organic layer was pooled. The pooled organic layer was concentrated under vacuum and purified using a silica column with DCM:methanol = 10:1 to give compound (B) (68 mg, 8.56%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.27 (td, 2H), 2.43 - 2.16 (m, 10H), 1.75 - 1.62 (m, 8H), 1.55 - 1.43 (m, 5H), 1.40 - 1.20 (m, 22H), 1.00 - 0.91 (m, 2H), 0.90 - 0.85 (m, 4H), 0.62 - 0.50 (m, 2H), 0.49 - 0.33 (m, 4H), 0.30 - 0.21 (m, 2H)

[0089] Example 3 According to the synthesis scheme shown in FIG. 3, a compound of the following formula (C) was produced.

[0090] [ka]

[0091] (1) Synthesis of 1-cyclopropylundecane-1-ol A 2000 mL three-neck RBF was charged with cyclopropanecarbaldehyde (27.0 g, 385 mmol, 1.00 eq) and THF (270 mL). The mixture was purged with nitrogen three times and cooled to -60 °C. Decyl magnesium bromide (1 M, 501 mL, 1.30 eq) was added, and the mixture was stirred at -60 °C for 16 h under a nitrogen atmosphere. The reactor was heated to 25 °C and poured into saturated aqueous NH4Cl (200 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (4 x 100 mL). The combined organic layers were concentrated in vacuo and purified on a silica column with petroleum ether: EtOAc = 10:1 to give 1-cyclopropylundecan-1-ol (56.0 g, 68.5%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 0.17 - 0.31 (m, 2 H) 0.43 - 0.57 (m, 2 H) 0.88 (t, 4 H) 1.26 (br s, 14 H) 1.37 - 1.49 (m, 2 H) 1.54 - 1.64 (m, 3 H) 2.85 (dt, 1 H)

[0092] (2) Synthesis of 1-cyclopropylundecyl 8-bromooctanoate A 1000 mL three-neck RBF was charged with 1-cyclopropylundecane-1-ol (24.0 g, 113 mmol, 1.00 eq), 8-bromooctanoic acid (32.8 g, 147 mmol, 1.30 eq), DCM (300 mL), EDCI (26.0 g, 136 mmol, 1.20 eq), and DMAP (16.6 g, 136 mmol, 1.20 eq) and purged with nitrogen three times. The mixture was stirred at 25 °C for 16 h, then poured into water (200 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (3 x 200 mL). The extracted organic layer was dried over Na2SO4, and the dried mixture was filtered and concentrated in vacuo. The residue after concentration was purified on a silica column with petroleum ether: EtOAc = 10:1 → 1:1 to give 1-cyclopropylundecyl 8-bromooctanoate (11.0 g, 23.3%). 1 H NMR (400 MHz, CHLOROFORM-d): δ 0.22 - 0.30 (m, 1 H) 0.33 - 0.40 (m, 1 H) 0.42 - 0.49 (m, 1 H) 0.50 - 0.58 (m, 1 H) 0.85 - 1.00 (m, 4 H) 1.20 - 1.38 (m, 20 H) 1.41 - 1.49 (m, 2 H) 1.58 - 1.68 (m, 4 H) 1.73 - 1.91 (m, 2 H) 2.25 - 2.37 (m, 2 H) 3.35 - 3.56 (m, 2 H) 4.21 - 4.35 (m, 1 H)

[0093] (3) Synthesis of the compound of formula (C) 1-Cyclopropylundecyl 8-bromooctanoate (3.00 g, 7.19 mmol, 1.00 eq) and methylamine solution (2 M in THF, 10.3 g, 331 mmol, 46.0 eq) were added to a 100 mL three-neck RBF and stirred at 50 °C for 16 hours. The mixture in the reactor was concentrated under vacuum, and then aqueous NaHCO3 solution was added to adjust the pH. Extraction was then performed with DCM, and the extracted organic layer was concentrated under vacuum. The residue after concentration was purified using a silica column with DCM:methanol = 10:1 → 1:1 to obtain compound (C) (2.00 g, 63.0%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 0.21 - 0.30 (m, 2 H) 0.37 (dq, 2 H) 0.42 - 0.49 (m, 2 H) 0.50 - 0.58 (m, 2 H) 0.84 - 0.98 (m, 8 H) 1.24 - 1.36 (m, 44 H) 1.51 (br s, 4 H) 1.59 - 1.68 (m, 8 H) 2.23 - 2.33 (m, 7 H) 2.34 - 2.44 (m, 4 H) 4.21 - 4.33 (m, 2 H)

[0094] Example 4 According to the synthesis scheme shown in FIG. 4, a compound of the following formula (D) was produced.

[0095] [ka]

[0096] (1) Synthesis of 1-cyclohexylnonan-1-ol A 1000 mL three-neck RBF was charged with cyclohexanecarbaldehyde (43.0 g, 383 mmol, 1.00 eq) and THF (430 mL), purged with nitrogen three times, and cooled to -65 °C. Octyl magnesium bromide (1 M in THF, 498 mL, 1.30 eq) was added, and the mixture was stirred at -65 °C for 1 h under a nitrogen atmosphere. The reactor was heated to 25 °C and poured into saturated aqueous NH4Cl (700 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3 x 400 mL). The combined organic layers were concentrated in vacuo and purified on a silica column with petroleum ether:EtOAc = 10:1 → 1:10 to give 1-cyclohexylnonan-1-ol (12.0 g, 53.0 mmol, 13.8%) as a colorless oil. 1 HNMR (400 MHz, CHLOROFORM-d): δ 3.41 - 3.31 (m, 1H), 1.84 - 1.73 (m, 3H), 1.70 - 1.63 (m, 2H), 1.48 (br d, 3H), 1.36 - 1.21 (m, 15H), 1.18 - 1.00 (m, 3H), 0.94 - 0.84 (m, 3H)

[0097] (2) Synthesis of 1-cyclohexylnonyl 8-bromooctanoate To a 250 mL three-neck RBF, 1-cyclohexylnonan-1-ol (7.00 g, 30.9 mmol, 1.00 eq) was added followed by DCM (70 mL). Then, 8-bromooctanoic acid (8.28 g, 37.1 mmol, 1.20 eq), EDCI (7.11 g, 37.1 mmol, 1.20 eq), DMAP (755 mg, 6.18 mmol, 0.20 eq), and EtN (6.26 g, 61.8 mmol, 2.00 eq) were added and mixed. The mixture was stirred at 25 °C for 16 h and purged with nitrogen three times. The reaction mixture was filtered through a plug of Celite, and the filtrate was concentrated in vacuo. The residue after concentration was purified on a silica column with petroleum ether: EtOAc = 10:1 → 1:100 to give 1-cyclohexylnonyl 8-bromooctanoate (3.50 g, 8.11 mmol, 26.2%) as a yellow oil. 1HNMR (400 MHz, CHLOROFORM-d): δ 4.07 (t, 2H), 3.41 (t, 2H), 2.30 (t, 2H), 1.91 - 1.80 (m, 2H), 1.67 - 1.58 (m, 4H), 1.47 - 1.41 (m, 2H), 1.37 - 1.26 (m, 16H), 0.91 - 0.87 (m, 3H)

[0098] (3) Synthesis of Compound of Formula (D) To a 100 mL three-neck RBF, 1-cyclohexylnonyl 8-bromooctanoate (1.50 g, 3.48 mmol, 1.00 eq) was added, followed by methylamine in THF (CHNH in THF) (15.6 g, 151 mmol, 30% purity, 43.5 eq). The mixture was purged with nitrogen three times and stirred at 50 °C for 16 h. After stirring, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified using a silica column with DCM:MeOH = 100:1 → 10:1 to give compound of formula (D) (0.13 g, 178 μmol, 5.11% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.81 - 4.69 (m, 2H), 2.30 (br t, 8H), 2.22 (br s, 3H), 1.76 - 1.71 (m, 4H), 1.69 - 1.60 (m, 12H), 1.53 - 1.43 (m, 10H), 1.35 - 1.22 (m, 40H), 1.05 - 0.97 (m, 4H), 0.88 (br t, 6H)

[0099] Example 5 According to the synthesis scheme shown in FIG. 5, the compound of the following formula (E) was produced.

[0100] [ka]

[0101] (1) Synthesis of 1-cyclopropylnonan-1-ol To a 1000 mL three-neck RBF, cyclopropanecarbaldehyde (46.0 g, 656 mmol, 1.00 eq) was added followed by THF. Octyl magnesium bromide (2.00 M, 492 mL, 1.50 eq) was added under a nitrogen atmosphere. The mixture was stirred at -65 °C for 3 h, then saturated aqueous NH4Cl (700 mL) was added at 15 °C, and the organic and aqueous layers were separated. The aqueous layer was further extracted with EtOAc (200 mL x 3). The combined organic layer was concentrated in vacuo and purified on a silica column with petroleum ether: EtOAc = 100:1 to give 1-cyclopropylnonan-1-ol (59.5 g, 49.2%) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 2.63 (td, 1H), 1.47 - 1.31 (m, 5H), 1.29 - 1.09 (m, 6H), 0.73 - 0.61 (m, 6H), 0.37 - 0.19 (m, 3H), 0.10 - 0.06 (m, 3H)

[0102] (2) Synthesis of 1-cyclopropylnonyl 8-bromooctanoate A 1000 mL three-neck RBF was charged with DCM (600 mL), 1-cyclopropylnonan-1-ol (59.5 g, 325 mmol, 1.00 eq), 8-bromooctanoic acid (94.4 g, 423 mmol, 1.30 eq), EDCI (93.6 g, 488 mmol, 1.50 eq), DMAP (39.8 g, 326 mmol, 1.00 eq), and TEA (32.9 g, 326 mmol, 45.3 mL, 1.00 eq) and stirred under nitrogen atmosphere at 25° C. for 16 h. The reaction mixture was concentrated in vacuo to give a residue. The resulting residue was purified on a silica column with petroleum ether: EtOAc = 100:1 → 1:1 to give 1-cyclopropylnonyl 8-bromooctanoate (21.0 g, 53.9 mmol, 16.6% yield) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d): δ 0.05 - 0.16 (m, 2 H) 0.16 - 0.34 (m, 2 H) 0.57 - 0.67 (m, 2 H) 0.67 -0.80 (m, 1 H) 1.02 (br s, 9 H) 1.05 (br s, 2 H) 1.07 - 1.15 (m, 6 H) 1.16 - 1.29 (m, 2 H) 1.34 - 1.44 (m, 4 H) 1.48 - 1.66(m, 2 H) 2.05 (t, 2 H) 3.06 - 3.33 (m, 2 H) 3.97 - 4.07 (m, 1 H)

[0103] (3) Synthesis of Compound of Formula (E) To a 100 mL three-necked RBF, 1-cyclopropylnonyl 8-bromooctanoate (4.78 g, 12.3 mmol, 2.50 eq), 2-aminoethanol (MEA) (0.30 g, 4.91 mmol, 1.00 eq), Na2CO3 (521 mg, 4.91 mmol, 1.00 eq) and EtOH (5 mL) were added, and the mixture was purged with nitrogen three times. The mixture was stirred at 95 °C for 16 h. The mixture in the reactor was concentrated in vacuo to give a residue. The resulting residue was purified using a silica column with DCM:MeOH = 100:1 to 10:1 to give compound of formula (E) (1.00 g, 1.47 mmol, 30.0% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.27 (td, 2H), 3.53 (t, 2H), 2.57 (t, 2H), 2.47 - 2.40 (m, 4H), 2.30 (t, 4H), 1.70 - 1.57 (m, 10H), 1.48 - 1.39 (m, 4H), 1.36 - 1.26 (m, 33H), 0.95 (dt, 2H), 0.89 (t, 6H), 0.60 - 0.42 (m, 4H), 0.41 - 0.22 (m, 4H)

[0104] Example 6 According to the synthesis scheme shown in FIG. 6, a compound of the following formula (F) was produced.

[0105] [ka]

[0106] (1) Synthesis of 2-cyclopropyldecanoic acid 2-Cyclopropylacetic acid (25.0 g, 250 mmol, 1.00 eq) was added to a 2000 mL three-neck RBF, followed by THF (250 mL) and cooling with nitrogen. Sodium hydride (NaH) (11.0 g, 275 mmol, 60% purity, 1.10 eq) was then added and stirred at 0 °C for 30 min. Lithium diisopropylamide (LDA) (2 M, 137 mL, 1.10 eq) was then added at the same temperature and under the same conditions and stirred for 30 min. 1-Iodooctane (60.0 g, 250 mmol, 1.00 eq) was then added at 25 °C and stirred at 45 °C for 12 h under a nitrogen atmosphere. The reactor was neutralized with 100 mL of water and 1 M HCl (600 mL, pH = 4) and extracted with EtOAc (300 mL x 3). The extracted organic layer was dried over anhydrous NaSO and concentrated in vacuo, and the residue was purified on a silica column with petroleum ether: EtOAc = 20:1 → 5:1 to give 2-cyclopropyldecanoic acid (42.6 g, 201 mmol, 80.4% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 11.88 (s, 1H), 1.84 - 1.70 (m, 1H), 1.70 - 1.54 (m, 2H), 1.42 - 1.19 (m, 12H), 1.00 - 0.81 (m, 4H), 0.63 - 0.45 (m, 2H), 0.32 (qd, 1H), 0.23 - 0.10 (m, 1H)

[0107] (2) Synthesis of 7-bromoheptyl 2-cyclopropyldecanoate To a 2000 mL three-neck RBF, 2-cyclopropyldecanoic acid (10.0 g, 47.1 mmol, 1.00 eq), 7-bromoheptan-1-ol (11.0 g, 56.5 mmol, 1.20 eq), EDCI (11.7 g, 61.2 mmol, 1.30 eq), and DMAP (5.75 g, 47.1 mmol, 1.00 eq) were added along with DCM (100 mL), and the mixture was purged with nitrogen three times. The mixture was stirred under a nitrogen atmosphere at 25 °C for 16 h. After that, the reaction mixture was warmed to 25 °C and poured into water (100 mL). The organic and aqueous layers were separated. The aqueous layer was extracted with DCM (3 x 100 mL). The organic layer was collected, concentrated in vacuo, dried over anhydrous Na2SO4, and filtered. The residue after filtration was purified on a silica column with petroleum ether: EtOAc = 20:1 → 5:1 to give 7-bromoheptyl 2-cyclopropyldecanoate (9.40 g, 24.1 mmol, 51.2%) as a pale yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.10 (t, J = 6.6 Hz, 2H), 3.42 (t, 2H), 1.89 - 1.84 (m, 1H), 1.81 - 1.51 (m, 6H), 1.50 - 1.35 (m, 6H), 1.27 (br s, 12H), 0.89 (t, 4H), 0.61 - 0.37 (m, 2H), 0.24 (s, 1H), 0.13 (qd, 1H)

[0108] (3) Synthesis of 7-(methylamino)heptyl 2-cyclopropyldecanoate To a 100 mL three-neck RBF, 7-bromoheptyl 2-cyclopropyldecanoate (4.00 g, 10.3 mmol, 1.00 eq) and methylamine (2 M in THF, 185 mL, 36.0 eq) were added, and the mixture was stirred at 50 °C for 16 h under a nitrogen atmosphere. The stirred reaction mixture was concentrated in vacuo and extracted with DCM (30 mL x 3), and the organic layer was saved. The saved organic layer was concentrated in vacuo and purified on a silica column with DCM:methanol = 20:1 → 10:1 to give 7-(methylamino)heptyl 2-cyclopropyldecanoate (0.45 g, 1.33 mmol, 12.9%) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.19 - 3.97 (m, 2H), 2.59 (t, 2H), 2.45 (s, 3H), 1.79 - 1.69 (m, 1H), 1.67 - 1.46 (m, 6H), 1.43 - 1.19 (m, 18H), 0.88 (t, 4H), 0.60 - 0.40 (m, 2H), 0.30 - 0.06 (m, 2H)

[0109] (4) Synthesis of Compound of Formula (F) To a 50 mL three-neck RBF was added 7-(methylamino)heptyl 2-cyclopropyldecanoate (0.40 g, 1.18 mmol, 1.00 eq), 7-bromoheptyl 2-cyclopropyldecanoate (0.60 g, 1.53 mmol, 1.30 eq) and Na2CO3 (0.25 g, 2.36 mmol, 2.00 eq) in dioxane (2 mL). The mixture was stirred at 100 °C for 16 h, cooled, poured into water (5 mL), and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was concentrated in vacuo, washed with saturated aqueous Na2CO3 (5 mL), dried over anhydrous Na2SO4, and filtered. The residue after concentration was purified using a silica column with DCM:methanol=20:1→10:1 to obtain the compound of formula (F) (0.36 g, 556 μmol, 47.2%) as a pale yellow oil. 1H NMR: (400 MHz, CHLOROFORM-d) δ 4.09 (dt, 4H), 2.72 - 2.07 (m, 7H), 1.73 (br dd, 2H), 1.67 - 1.50 (m, 12H), 1.40 - 1.23 (m, 36H), 0.88 (br t, 8H), 0.59 - 0.50 (m, 2H), 0.45 (s, 2H), 0.24 (s, 2H), 0.13 (br d, 2H)

[0110] Example 7 According to the synthesis scheme shown in FIG. 7, the compound of the following formula (G) was produced.

[0111] [ka]

[0112] (1) Synthesis of 1-cyclopropylheptan-1-ol A 2000 mL three-neck RBF was charged with cyclopropanecarbaldehyde (27.0 g, 385 mmol, 1.00 eq) and THF (500 mL). To this mixture, hexylmagnesium bromide (1 M in THF, 500 mL, 1.30 eq) was slowly added at 0 °C. The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into saturated aqueous NH4Cl, and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (500 mL x 3). The organic layers were combined and concentrated in vacuo. The residue was purified on a silica column with petroleum ether:EtOAc = 50:1 → 10:1 to give 1-cyclopropylheptan-1-ol (46 g, 294.37 mmol, 76.4% yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 2.86 (td, 1H), 1.67 - 1.38 (m, 6H), 1.36 - 1.27 (m, 6H), 0.91 - 0.87 (m, 3H), 0.59 - 0.42 (m, 2H), 0.32 - 0.17 (m, 2H)

[0113] (2) Synthesis of 1-cyclopropylheptyl 8-bromooctanoate To a 2000 mL three-neck RBF, 1-cyclopropylheptan-1-ol (10.0 g, 63.9 mmol, 1.00 eq) and 8-bromooctanoic acid (12.5 g, 63.9 mmol, 1.00 eq) in DCM (100 mL) were added. Next, DMAP (10.2 g, 83.19 mmol, 1.30 eq) and EDCI (15.9 g, 83.2 mmol, 1.30 eq) were added to the mixture. The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into HO (100 mL), extracted, and then re-extracted with DCM (3 x 100 mL). The organic layer was saved and concentrated in vacuo. The residue after concentration was purified on a silica column with petroleum ether: EtOAc = 50:1 → 10:1 to give 1-cyclopropylheptyl 8-bromooctanoate (7.50 g, 22.5 mmol, 35.1% yield) as a colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.28 (td, 1H), 3.59 - 3.36 (m, 2H), 2.35 - 2.26 (m, 2H), 1.92 - 1.72 (m, 2H), 1.69 - 1.60 (m, 4H), 1.50 - 1.41 (m, 2H), 1.37 - 1.24 (m, 12H), 1.01 - 0.84 (m, 4H), 0.62 - 0.50 (m, 1H), 0.50 - 0.41 (m, 1H), 0.37 (td, 1H), 0.26 (qd, 1H)

[0114] (3) Synthesis of Compound of Formula (G) To a 500 mL three-neck RBF, MeNH2 (2 M in THF, 200.76 mL, 48.4 eq) was added, and 1-cyclopropylheptyl 8-bromooctanoate (3.00 g, 8.30 mmol, 1.00 eq) was added to the flask under a nitrogen atmosphere. The mixture was stirred at 80 °C for 16 h, and then the solvent was evaporated. The residue after evaporation was purified on a silica column with petroleum ether: EtOAc = 50:1 → 10:1 to give compound of formula (G) (0.50 g, 844 μmol, 10.2% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d): δ 0.26 (dq, 2 H) 0.34 - 0.40 (m, 2 H) 0.42 - 0.49 (m, 2 H) 0.50 - 0.58 (m, 2 H) 0.89 (br t, 6 H) 0.93 - 0.98 (m, 2 H) 1.26 - 1.34 (m, 26 H) 1.47 (br s, 4 H) 1.57 - 1.70 (m, 10 H) 2.13 - 2.41 (m, 11 H) 4.27 (dt, 2 H)

[0115] Example 8 The compound of formula (H) below was produced according to the synthesis scheme shown in Figure 8. The synthesis method was the same as in Example 5, except that "cyclopropanecarbaldehyde" was replaced with "cyclopentanecarbaldehyde" and the same molar equivalents were used.

[0116] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.26 (td, 2H), 3.54 (t, 2H), 2.55 (t, 2H), 2.50 - 2.41 (m, 4H), 2.28 (t, 4H), 1.70 - 1.56 (m, 10H), 1.49 - 1.39 (m, 4H), 1.35 - 1.21 (m, 49H), 0.95 (dt, 2H), 0.89 (t, 6H)

[0117] Example 9 The compound of formula (I) below was produced according to the synthesis scheme shown in Figure 9. The synthesis method was the same as in Example 5, except that "cyclopropanecarbaldehyde" was replaced with "cyclopentanecarbaldehyde," and "octyl magnesium bromide" was replaced with "7-methyloctyl magnesium bromide," and the same molar equivalents were used.

[0118] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.28 (td, 2H), 3.50 (t, 2H), 2.58 (t, 2H), 2.49 - 2.40 (m, 4H), 2.30 (t, 4H), 1.71 - 1.60 (m, 10H), 1.50 - 1.41 (m, 4H), 1.35 - 1.20 (m, 49H), 0.97 (dt, 2H), 0.92 (t, 6H)

[0119] Example 10 The compound of formula (J) below was produced according to the synthesis scheme shown in Figure 10. The synthesis method was the same as in Example 7, except that "hexyl magnesium bromide" was replaced with "(3,7-dimethyloxyl) magnesium bromide" and the same molar equivalents were used.

[0120] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): 4.19 (dt, 2 H), 2.41 - 2.15 (m, 11 H), 1.71 - 1.51 (m, 10 H), 1.47 (br s, 4 H), 1.33 - 1.25 (m, 22 H), 0.98 - 0.93 (m, 2 H), 0.91 - 0.88 (m, 18H), 0.58 - 0.50 (m, 2 H), 0.49 - 0.42 (m, 2 H), 0.40 - 0.34 (m, 2 H), δ 0.26 (dq, 2 H)

[0121] Example 11 The compound of formula (K) below was produced according to the synthesis scheme shown in Figure 11. The synthesis method was the same as in Example 5, except that "2-aminoethanol" was replaced with "2-methoxyethan-1-amine" and the same molar equivalents were used.

[0122] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.25 (td, 2H), 3.69 (t, 2H), 3.35 (s, 3H), 2.60 (t, 2H), 2.45 - 2.39 (m, 4H), 2.38 (t, 4H), 1.72 - 1.57 (m, 10H), 1.43 - 1.34 (m, 4H), 1.30 - 1.25 (m, 33H), 0.95 (dt, 2H), 0.88 (t, 6H), 0.60 - 0.42 (m, 4H), 0.41 - 0.22 (m, 4H)

[0123] Example 12 The compound of formula (L) below was prepared according to the synthesis scheme shown in Figure 12. The synthesis method was the same as in Example 3. "1-cyclopropylundecyl 8-bromooctanoate" and "1-cyclopropylnonyl 10-bromodecanoate" were each prepared, and then reacted with "methylamine" to prepare the compound of formula (L).

[0124] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.28 (td, 2H), 2.41 (br t, 8H), 2.22 (s, 3H), 1.80 - 1.66 (m, 8H), 1.50 - 1.39 (m, 4H), 1.39 - 1.23 (m, 48H), 1.02 (m, 2H), 0.87 (m, 6H), 0.61 - 0.22 (m, 8H)

[0125] Example 13 The compound of formula (M) below was prepared according to the synthesis scheme shown in Figure 13. The synthesis method was the same as in Example 5. "1-cyclopropylundecyl 8-bromooctanoate" and "1-cyclohexylnonyl 8-bromooctanoate" were each prepared, and then reacted with "2-aminoethanol" to prepare the compound of formula (M).

[0126] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.30-4.27 (m, 2H), 3.52 (t, 2H), 2.57 (t, 2H), 2.47 - 2.41 (m, 4H), 2.31-2.29 (m, 4H), 1.70 - 1.57 (m, 8H), 1.48 - 1.41 (m, 4H), 1.36 - 1.26 (m, 57H), 0.94 (dt, 1H), 0.88 (t, 6H), 0.60 - 0.42 (m, 2H), 0.41 - 0.22 (m, 2H)

[0127] Example 14 The compound of formula (N) below was produced according to the synthesis scheme shown in Figure 14. The synthesis method was the same as in Example 1, except that "cyclopropanecarbaldehyde" was replaced with "bicyclo[2.2.1]heptane-2-carbaldehyde" and the same molar equivalents were used.

[0128] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ 4.35 (td, 2H), 2.35-2.29 (m, 8H), 2.20 (s, 3H), 2.18 - 2.15 (m, 2H), 1.75 - 1.66 (m, 8H), 1.54 - 1.23 (m, 60H), 0.89 (t, 6H)

[0129] Example 15 The compound of formula (O) was prepared according to the synthesis scheme shown in Figure 15. The synthesis method was the same as in Example 5, except that "cyclopropanecarbaldehyde" was replaced with "bicyclo[3.1.1]heptane-3-carbaldehyde" and the same molar equivalents were used.

[0130] [ka] 1 H NMR (400 MHz, CHLOROFORM-d): δ = 4.40 (td, 2H), 3.54 (t, 2H), 2.56 (t, 2H), 2.47 - 2.40 (m, 4H), 2.30 (t, 4H), 2.22 (m, 2H), 1.71 - 1.58 (m, 10H), 1.48 - 1.26 (m, 54H), 0.99 - 0.79 (m, 10H)

[0131] Preparation example of drug delivery composition: Preparation of formulations using compounds of formulae (A to G) 1. Preparation of Raw Materials The raw materials required for manufacturing the formulation were dissolved in each dilution solvent to prepare the required concentration according to Table 1. When dissolving, the raw materials were kept at room temperature and dissolved by adding the solvent.

[0132] [Table 1]

[0133] 2.Mixing of raw materials The raw materials were mixed in the required amounts so that the N / P ratio (amine groups of lipids:phosphate groups of mRNA) was 6, and the ratio of each compound of formulas (A-G): DOPE: cholesterol: DMG-PEG = 50:10:38.5:1.5. 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 mixed solution was concentrated by centrifugation at 4,000 rpm using an Amicon-Ultra tube filter (Merck Millipore, UFC505096 or UFC805024, pore size: 50K, volume: 15 mL). This was then diluted with PBS, centrifuged, and concentrated. This process was repeated to perform buffer exchange.

[0134] More specific steps are as follows: 1) Two autoclaved tubes were prepared (tubes (A) and (B)). 2) Each compound of formulae (A to G), DOPE, cholesterol, and DMG-PEG were added to tube (A) in order in molar amounts calculated according to the experimental conditions, and mixed by vortexing. 3) Ethanol was added to the ethanol phase 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), with the ratio calculated so that the total volume of the aqueous phase was three times that of the ethanol phase. 5) Tube (A) and tube (B) were mixed using microfluidics (Ignite, Precision Nanosystems). The operating conditions of the microfluidics were FRR (flow ratio) C:R = 3:1 and 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), and the process of concentration and dilution was repeated to remove excess ethanol, and finally concentrated to x mg / mL (theoretical concentration).

[0135] 3. Evaluation of the physical properties of the formulation 1) The particle characteristics of the manufactured formulation were confirmed using a particle size analyzer (dynamic light scattering, DLS), and the results are shown in Table 2 below. 2) The efficiency of entrapment of mRNA was confirmed by RiboGreen assay, and the results are shown in Table 2 below.

[0136] [Table 2]

Claims

1. A lipid having a structure represented by the following formula (1): 【Chemical 1】 (In the formula, M 1 and M 2 are each independently a divalent linker group, R 1 and R 2 are each independently a substituted or unsubstituted carbocyclic or heterocyclic group; R 3 is a hydrogen atom or a substituted or unsubstituted organic group optionally containing one or more heteroatoms, R 4 ~R 11 are each independently a hydrogen atom or a substituted or unsubstituted saturated or unsaturated hydrocarbon group, Me is a methyl group; a, b, c, and d are each independently an integer from 1 to 20.

2. M 1 and M 2 are each independently —C(O)O—, —OC(O)—, —OC(O)-M′-C(O)O—, —C(O)N(R′)—, —N(R′)C(O)—, —C(O)—, —C(S)—, —C(S)S—, —SC(S)—, —CH(OH)—, —P(O)(OR′)O—, —S(O) 2 -, -S-S-, arylene, and heteroarylene, wherein M' is a direct bond, C 1-13 Alkylene or C 2-13 alkenylene, and each R' is independently a hydrogen atom, C 1-18 Alkyl and C 2-18 alkenyl, R 1 and R 2 are each independently substituted or unsubstituted C 3-20 Cycloalkyl, substituted or unsubstituted C 3-20 Cycloalkenyl, substituted or unsubstituted C 6-20 Aryl, substituted or unsubstituted C 3-20 Heterocycloalkyl, substituted or unsubstituted C 3-20 heterocycloalkenyl, and substituted or unsubstituted C 3-20 heteroaryl; R 3 represents a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclic group, -(CH 2 ) n Q, -(CH 2 ) n CHQR, -CHQR and -CQ(R) 2 wherein each R is independently selected from the group consisting of a hydrogen atom, C 1-3 Alkyl and C 2-3 alkenyl; Q is a carbocyclic group, a heterocyclic group, —OR, —O(CH 2 ) n N (R) 2 , -C(O)OR, -OC(O)R, -CX 3 , -CX 2 H, -CXH 2 , -CN, -N(R) 2 , -C(O)N(R) 2 , -N(R)C(O)R, -N(R)S(O) 2 R, -N(R)C(O)N(R) 2 , -N(R)C(S)N(R) 2 , -N(R)R 12 , N(R)S(O) 2 R 12 , -O(CH 2 ) n OR, -N(R)C(=NR 13 ) N (R) 2 , -N(R)C(=CHR 13 ) N (R) 2 , -OC(O)N(R) 2 , -N(R)C(O)OR, -N(OR)C(O)R, -N(OR)S(O) 2 R, -N(OR)C(O)OR, -N(OR)C(O)N(R) 2 , -N(OR)C(S)N(R) 2 , -N(OR)C(=NR 13 ) N (R) 2 , -N(OR)C(=CHR 13 ) N (R) 2 , -C(=NR 13 ) N (R) 2 , -C(=NR 13 )R, -C(O)N(R)OR and -C(R)N(R) 2 C(O)OR, where each n is independently an integer from 1 to 5; 12 is C 3-6 selected from the group consisting of carbocyclic and heterocyclic groups; R 13 H, CN, NO 2 , C 1-6 Alkyl, —OR, —S(O) 2 R, -S(O) 2 N (R) 2 , C 2-6 Alkenyl, C 3-6 and each R is independently selected from the group consisting of a hydrogen atom, a C 1-3 Alkyl and C 2-3 alkenyl, and each X is independently selected from the group consisting of F, CI, BR, and I, with the proviso that R 3 Ga-(CH 2 ) n Q, -(CH 2 ) n CHQR, -CHQR or -CQ(R) 2 (i) when n is 1, 2, 3, 4 or 5, Q is -N(R) 2 or (ii) when n is 1 or 2, Q is not a 5-, 6-, or 7-membered heterocycloalkyl; R 4 ~R 11 are each independently a hydrogen atom, C 1-3 Alkyl and C 2-3 alkenyl, 2. The lipid of claim 1, wherein a, b, c, and d are each independently an integer from 1 to 15.

3. M 1 and M 2 are each independently selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)-M′-C(O)O—, —C(O)N(R′)—, —N(R′)C(O)— and —C(O)—, wherein M′ and R′ are as defined in claim 2; R 1 and R 2 are each independently substituted or unsubstituted C 3-20 Cycloalkyl and substituted or unsubstituted C 3-20 heterocycloalkyl; R 3 represents a hydrogen atom, a substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 is selected from the group consisting of carbocyclic groups; R 4 ~R 11 are each independently a hydrogen atom or C 1-3 is alkyl, 2. The lipid of claim 1, wherein a, b, c, and d are each independently an integer from 3 to 11.

4. M 1 and M 2 are each independently —C(O)O— or —OC(O)—, R 1 and R 2 are each independently substituted or unsubstituted C 3-6 is cycloalkyl, R 3 is a hydrogen atom or an unsubstituted C 1-3 is alkyl, R 4 ~R 11 is a hydrogen atom, 2. The lipid of claim 1, wherein a, b, c, and d are each independently an integer from 5 to 9.

5. The lipid according to claim 1, wherein the lipid has a structure selected from the following formulas (A to O): 【Chemistry 2】 【Chemistry 3】

6. A method for producing a lipid having a structure represented by formula (1'), 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 a compound of formula (f). 【Chemistry 4】 (In the formula, M 1 , R 1 , R 3 , R 4 , R 5 , R 8 , R 9 , Me, a, and b are as defined in claim 1, and each X is independently selected from the group consisting of F, CI, BR, and I.

7. A method for producing a lipid having a structure represented by formula (1), 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) A step of reacting the compound of formula (e') and the compound of formula (e) obtained in claim 6 with a compound of formula (f). 【Chemistry 5】 (In the formula, M 1 , M 2 , R 1 ~R 11 , Me, a, b, c, and d are as defined in claim 1, and each X is independently selected from the group consisting of F, CI, BR, and I.

8. A method for producing a lipid having a structure represented by formula (1'), comprising the steps of: (1) reacting a compound of formula (i) with a compound of formula (ii) to obtain a compound of formula (iii); (2) reacting a compound of formula (iii) with a compound of formula (iv) to obtain a compound of formula (v); (3) reacting a compound of formula (v) with a compound of formula (vi) to obtain a compound of formula (vii); and (4) reacting the compound of formula (v) with a compound of formula (vii). 【Chemistry 6】 (In the formula, M 1 , R 1 , R 3 , R 4 , R 5 , R 8 , R 9 , Me, a, and b are as defined in claim 1, and each X is independently selected from the group consisting of F, CI, BR, and I.

9. A method for producing a lipid having a structure represented by formula (1), comprising the steps of: (1) reacting a compound of formula (i') with a compound of formula (ii') to obtain a compound of formula (iii'); (2) reacting the compound of formula (iii') with the compound of formula (iv') to obtain the compound of formula (v'); (3) reacting a compound of formula (v') with a compound of formula (vi) to obtain a compound of formula (vii'); and (4) A step of reacting the compound of formula (vii') with the compound of formula (v) obtained in claim 8. 【Chemistry 7】 (In the formula, M 1 , M 2 , R 1 ~R 11 , Me, a, b, c, and d are as defined in claim 1, and each X is independently selected from the group consisting of F, CI, BR, and I.

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

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