Lipids having amide and ester functional groups and methods of making same

Abstract

The present invention relates to a lipid having an amide functional group and an ester functional group and a method for preparing the same, and more particularly, to an ionized lipid which forms a complex with an anionic drug, and which can be used for drug delivery due to a specific structure having an amide functional group and an ester functional group, and a method for preparing the same.

Description

Technical Field

[0001] The present invention relates to a lipid having an amide functional group and an ester functional group and a preparation method thereof, and more specifically, to an ionized lipid and a preparation method thereof. The ionized lipid forms a complex with an anionic drug and can be used for drug delivery due to the specific structure of the amide and ester functional groups. Background Art

[0002] In the therapy using anionic drugs including nucleic acids, safe and effective drug delivery technology has been studied for a long time, and various carriers and technologies for delivery have been developed. Carriers are mainly divided into viral vectors utilizing adenovirus, retrovirus, etc. and non-viral vectors utilizing cationic lipids, cationic polymers, etc. Known viral vectors are exposed to risks such as nonspecific immune responses, and due to the complexity of the production process, there are many problems in commercialization. Therefore, recent research is being conducted in the direction of improving these shortcomings by using non-viral vectors. Compared with viral vectors, non-viral vectors have the advantages of less side effects in terms of safety in vivo and lower production costs in terms of economy.

[0003] The representative non-viral vector for delivering nucleic acid substances is the complex (cationic liposome (lipoplex)) of cationic lipid and nucleic acid and the complex (complex (polyplex)) of polycation (polycation) polymer and nucleic acid. This cationic lipid or polycationic polymer form complex by the electrostatic interaction with anionic drug to stabilize anionic drug and improve intracellular delivery, and for these reasons, various researches (De Paula D, Bentley MV, Mahato RI, Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting, RNA 13 (2007) 431-56; Gary DJ, Puri N, Won YY, Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery, J Controlrelease 121 (2007) 64-73) have been carried out to it.

[0004] However, polycationic polymers have cytotoxicity due to the multivalent cationic charge, which has problems in practical use, and nucleic acid-cationic lipid complexes have low stability in blood and are difficult to use in actual organisms. In addition, the disadvantages of ionic liposomes containing cationic lipids, neutral lipids and fusogenic lipids are that the synthesis method of the cationic lipids used is complicated, cytotoxic, and the efficiency of intracellular nucleic acid delivery is low. Summary of the invention

[0005] Technical issues to be solved

[0006] The object of the present invention is to provide a lipid with a specific structure which can be used for drug delivery because it can easily form a complex with anionic drugs and a preparation method thereof.

[0007] Technical Solution

[0008] The first aspect of the present invention provides a lipid having a structure selected from the following, or an ionized form thereof:

[0009]

[0010] as well as

[0011]

[0012] in,

[0013] In the above structures, at least two of the R groups are Rx, and the remaining R groups are Ry, wherein

[0014] Rx are each independently selected from , , and , 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, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group,

[0015] Ry is each independently H or a substituted or unsubstituted alkyl group, wherein two Ry groups other than H may be linked together with the nitrogen atom to which they are attached to form a ring structure,

[0016] L is each independently a substituted or unsubstituted alkylene group, and may optionally have an ether bond (—O—), a thioether bond (—S—), or a disulfide bond (—SS—) in its structure.

[0017] According to a specific embodiment of the present invention, the Ry can be independently H or C 1-20Alkyl, wherein the alkyl groups are each independently unsubstituted or can be selected from -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 The carbocyclyl and optionally substituted C 3-20 The heterocyclic group may be substituted with one or more heteroatoms selected from N, O and S (e.g., 1-3), and two Ry groups other than H may be linked together with the nitrogen atom to which they are linked, thereby forming a ring structure optionally having one or more heteroatoms selected from N and O.

[0018] According to a specific embodiment of the present invention, the L can be independently C 1-20 Alkylene, which may be each independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-20 The heterocyclic group may have one or more heteroatoms selected from N, O and S (eg, 1 to 3).

[0019] More specifically, the Rx are each independently selected from , , and , wherein a, b and c can each independently be an integer from 2 to 20 or from 2 to 15, and R1 can be a substituted or unsubstituted saturated or unsaturated divalent C 1-12 Hydrocarbyl, R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 Hydrocarbon, represents a substituted or unsubstituted methylene group.

[0020] More specifically, the Ry can each independently be H or C 1-10 Alkyl, wherein the alkyl groups are each independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-10The heterocyclic group may have one or more (e.g., 1-3) heteroatoms selected from N, O and S, and two Ry groups other than H are connected together with the nitrogen atom to which they are connected, thereby forming a ring structure optionally having one or more heteroatoms selected from N and O.

[0021] More specifically, the L can be each independently C 1-10 Alkylene, each of which is independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-10 The heterocyclic group may have one or more heteroatoms selected from N, O and S (eg, 1 to 3).

[0022] More specifically, the Rx are each independently selected from , and , wherein a, b and c can each independently be an integer from 3 to 12, and R1 can be a substituted or unsubstituted C 1-12 Alkylene, substituted or unsubstituted C 2-12 Alkenylene or substituted or unsubstituted C 2-12 Alkyne, R2 can be substituted or unsubstituted C 2-24 Alkenyl or substituted or unsubstituted C 2-24 Alkynyl, represents a substituted or unsubstituted methylene group.

[0023] More specifically, the Ry can each independently be H or C 1-6 Alkyl, wherein the alkyl groups may be each independently unsubstituted or substituted by one or more selected from -OH and -NH2, and two Ry groups other than H may be linked together with the nitrogen atom to which they are linked, thereby forming a ring structure optionally having one or more heteroatoms selected from N and O.

[0024] More specifically, the L can be each independently an unsubstituted C 1-6 Alkylene.

[0025] More specifically, the lipid may have any one structure selected from the following Chemical Formulae A to V:

[0026]

[0027]

[0028]

[0029] The second aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-1, comprising the following steps: (1) reacting a compound of Chemical Formula a with a compound of Chemical Formula b to obtain a compound of Chemical Formula c; (2) reacting the compound of Chemical Formula c with a compound of Chemical Formula d to obtain a compound of Chemical Formula e; and (3) reacting the compound of Chemical Formula e with a compound of Chemical Formula f, and then deprotecting the reaction product:

[0030] [Chemical formula a]

[0031] H2N-(CH2) a -C(=O)OH

[0032] [Chemical formula b]

[0033] OH-R'

[0034] [Chemical formula c]

[0035] H2N-(CH2) a -C(=O)OR'

[0036] [Chemical formula d]

[0037]

[0038] [Chemical formula e]

[0039] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0040] [Chemical formula f]

[0041] H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3

[0042] [Chemical formula 1-1]

[0043] H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2

[0044] in,

[0045] R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0046] a, b and c are each independently an integer from 2 to 20,

[0047] X is selected from the group consisting of F, CI, Br and I.

[0048] The third aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-2, comprising the step of reacting the compound of Chemical Formula e obtained in the second aspect of the present invention with the compound of Chemical Formula g:

[0049] [Chemical formula e]

[0050] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0051] [Chemical formula g]

[0052] H2N-(CH2) 1-20 -N(C 1-20 Alkyl)2

[0053] [Chemical formula 1-2]

[0054] (C 1-20 Alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2

[0055] in,

[0056] R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0057] a, b and c are each independently an integer from 2 to 20.

[0058] The fourth aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-3, comprising the step of reacting the compound of Chemical Formula E obtained in the second aspect of the present invention with the compound of Chemical Formula H:

[0059] [Chemical formula e]

[0060] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0061] [Chemical formula h]

[0062] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl)

[0063] [Chemical formula 1-3]

[0064] AN(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A

[0065] in,

[0066] R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0067] A is -CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R',

[0068] a, b and c are each independently an integer from 2 to 20,

[0069] X is selected from the group consisting of F, CI, Br and I.

[0070] A fifth aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-4, comprising the following steps: (1) reacting a compound of Chemical Formula a with a compound of Chemical Formula b' to obtain a compound of Chemical Formula c'; (2) reacting a compound of Chemical Formula c' with a compound of Chemical Formula d to obtain a compound of Chemical Formula e'; and (3) reacting a compound of Chemical Formula e' with a compound of Chemical Formula h:

[0071] [Chemical formula a]

[0072] H2N-(CH2) a -C(=O)OH

[0073] [Chemical formula b']

[0074] OH-R2

[0075] [Chemical formula c']

[0076] H2N-R1-C(=O)O-R2

[0077] [Chemical formula d]

[0078]

[0079] [Chemical formula e']

[0080] H2C=CH-C(=O)-HN-R1-C(=O)O-R2

[0081] [Chemical formula h]

[0082] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl)

[0083] [Chemical formula 1-4]

[0084] A'-N(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A'

[0085] in,

[0086] A' is -CH2-CH2-C(=O)-HN-R1-C(=O)O-R2,

[0087] R1 is independently a substituted or unsubstituted saturated or unsaturated divalent hydrocarbon group,

[0088] R2 is independently a substituted or unsubstituted unsaturated monovalent hydrocarbon group,

[0089] a is an integer from 2 to 20,

[0090] X is selected from the group consisting of F, CI, Br and I.

[0091] A sixth aspect of the present invention provides a composition for drug delivery comprising the lipid according to the present invention.

[0092] Beneficial Effects

[0093] The lipid having a specific structure according to the present invention can easily form a complex with anionic drugs, and when the complex is applied, the drug can be effectively delivered to target biological tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 Schematic diagram of the reaction of the lipid synthesis process performed in Example 1.

[0095] Figure 2 Schematic diagram of the reaction of the lipid synthesis process performed in Example 2.

[0096] Figure 3 Schematic diagram of the reaction of the lipid synthesis process performed in Example 3.

[0097] Figure 4 Schematic diagram of the reaction of the lipid synthesis process performed in Example 4.

[0098] Figure 5 Schematic diagram of the reaction of the lipid synthesis process performed in Example 5.

[0099] Figure 6 Schematic diagram of the reaction of the lipid synthesis process performed in Example 6.

[0100] Figure 7 Schematic diagram of the reaction of the lipid synthesis process performed in Example 7.

[0101] Figure 8 Schematic diagram of the reaction of the lipid synthesis process performed in Example 8.

[0102] Fig. 9 Schematic diagram of the reaction of the lipid synthesis process performed in Example 9.

[0103] Fig.10 Schematic diagram of the reaction of the lipid synthesis process performed in Example 10.

[0104] Fig.11 Schematic diagram of the reaction of the lipid synthesis process performed in Example 11.

[0105] Fig.12 Schematic diagram of the reaction of the lipid synthesis process performed in Example 12.

[0106] Fig.13 Schematic diagram of the reaction of the lipid synthesis process performed in Example 13.

[0107] Fig.14 Schematic diagram of the reaction of the lipid synthesis process performed in Example 14.

[0108] Fig.15 Schematic diagram of the reaction of the lipid synthesis process performed in Example 15.

[0109] Fig.16 Schematic diagram of the reaction of the lipid synthesis process performed in Example 16.

[0110] Fig.17 Schematic diagram of the reaction of the lipid synthesis process performed in Example 17.

[0111] Fig.18 Schematic diagram of the reaction of the lipid synthesis process performed in Example 18.

[0112] Fig.19 Schematic diagram of the reaction of the lipid synthesis process performed in Example 19.

[0113] Fig. 20Schematic diagram of the reaction of the lipid synthesis process performed in Example 20.

[0114] Fig.21 Schematic diagram of the reaction of the lipid synthesis process carried out in Example 21.

[0115] Fig. 22 Schematic diagram of the reaction of the lipid synthesis process carried out in Example 22. DETAILED DESCRIPTION

[0116] Hereinafter, the present invention will be described in more detail.

[0117] The lipid provided according to the first aspect of the present invention has a structure selected from the following or is an ionized form of a structure selected from the following:

[0118]

[0119] as well as

[0120]

[0121] in,

[0122] In the above structures, at least 2 (more specifically 2-7) of the R groups are Rx, and the remaining R groups are Ry, wherein

[0123] Rx are each independently selected from , , and , 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, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group,

[0124] Ry is each independently H or a substituted or unsubstituted alkyl group, wherein two Ry groups other than H may be linked together with the nitrogen atom to which they are attached to form a ring structure,

[0125] L is each independently a substituted or unsubstituted alkylene group, and may optionally have an ether bond (—O—), a thioether bond (—S—), or a disulfide bond (—SS—) in its structure.

[0126] In the present specification, unless otherwise specified, a description of any group as "substituted or unsubstituted" means that the group is unsubstituted or is selected from -OH, a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-20Cycloalkyl, C 3-20 Heterocycloalkyl, C 6-20 Aryl or C 3-20 The heteroaryl group is substituted with one or more substituents.

[0127] According to a specific embodiment of the present invention, the Rx are each independently selected from , , and , wherein a, b and c can each independently be an integer from 2 to 20 or from 2 to 15, and R1 can be a substituted or unsubstituted saturated or unsaturated divalent C 1-12 Hydrocarbyl, R2 may be a substituted or unsubstituted unsaturated monovalent C 2-24 Hydrocarbon, represents a substituted or unsubstituted methylene group.

[0128] According to a specific embodiment of the present invention, a, b and c may be each independently an integer of 2 to 15, more specifically, each independently an integer of 3 to 12. Further specifically, a may be an integer of 5 to 7, and b and c may be each independently an integer of 3 to 11, but are not limited thereto.

[0129] According to a specific embodiment of the present invention, the Ry can be independently H or C 1-20 Alkyl, wherein the alkyl groups are each independently unsubstituted or selected from -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 or C 6-20 aryl) and optionally substituted C 3-20 Heterocyclic groups (e.g., C 3-20 Heterocycloalkyl or C 3-20 wherein the heterocyclic group may have one or more (e.g., 1 to 3) heteroatoms selected from N, O and S, and two Ry groups other than H may be connected together with the nitrogen atom to which they are connected, thereby forming a ring structure optionally having one or more heteroatoms selected from N and O. In addition, the alkyl or alkoxy group may be more specifically C 1-10 Alkyl or alkoxy, more specifically C 1-6 The group may be an alkyl group or an alkoxy group, but is not limited thereto.

[0130] According to a specific embodiment of the present invention, the L can be independently C 1-20Alkylene (more specifically C 1-10 Alkylene, further specifically C 1-6 alkylene), each of which is independently unsubstituted or may be selected from -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 or C 6-20 aryl) and optionally substituted C 3-20 Heterocyclic groups (e.g., C 3-20 Heterocycloalkyl or C 3-20 The heterocyclic group may have one or more heteroatoms (e.g., 1 to 3) selected from N, O and S. In addition, the alkyl or alkoxy group may be more specifically C 1-10 Alkyl or alkoxy, more specifically C 1-6 The group may be an alkyl group or an alkoxy group, but is not limited thereto.

[0131] More specifically, the Ry can each independently be H or C 1-10 Alkyl, wherein the alkyl groups are each independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-10 The heterocyclic group may have one or more (e.g., 1-3) heteroatoms selected from N, O and S, and two Ry 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.

[0132] More specifically, the L can be each independently C 1-10 Alkylene, each of which is independently unsubstituted, or may be selected from -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 The carbocyclyl and optionally substituted C 3-10 The heterocyclic group may have one or more heteroatoms selected from N, O and S (eg, 1 to 3).

[0133] More specifically, the Rx are each independently selected from , and , wherein a, b and c can each independently be an integer from 3 to 12, and R1 can be a substituted or unsubstituted C 1-12 Alkylene, substituted or unsubstituted C 2-12 Alkenylene or substituted or unsubstituted C 2-12 Alkyne, R2 can be substituted or unsubstituted C 2-24 Alkenyl or substituted or unsubstituted C 2-24 Alkynyl, represents a substituted or unsubstituted methylene group.

[0134] More specifically, the Ry can each independently be H or C 1-6 Alkyl, wherein the alkyl groups are each independently unsubstituted or may be substituted with one or more selected from -OH and -NH2, and two Ry groups other than H may be linked together with the nitrogen atom to which they are linked, thereby forming a ring structure optionally having one or more heteroatoms selected from N and O.

[0135] More specifically, the L can be each independently an unsubstituted C 1-6 Alkylene.

[0136] Specifically, the lipid may have any structure selected from the following:

[0137] .

[0138] In the above structures, R1 to R7 are each independently selected from , , and , 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, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group.

[0139] More specifically, the lipid may have any one structure selected from the following Chemical Formulae A to V:

[0140]

[0141]

[0142]

[0143] The second aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-1, comprising the following steps: (1) reacting a compound of Chemical Formula a with a compound of Chemical Formula b to obtain a compound of Chemical Formula c; (2) reacting the compound of Chemical Formula c with a compound of Chemical Formula d to obtain a compound of Chemical Formula e; and (3) reacting the compound of Chemical Formula e with a compound of Chemical Formula f to deprotect the reaction product:

[0144] [Chemical formula a]

[0145] H2N-(CH2) a -C(=O)OH

[0146] [Chemical formula b]

[0147] OH-R'

[0148] [Chemical formula c]

[0149] H2N-(CH2) a -C(=O)OR'

[0150] [Chemical formula d]

[0151]

[0152] [Chemical formula e]

[0153] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0154] [Chemical formula f]

[0155] H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3

[0156] [Chemical formula 1-1]

[0157] H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2

[0158] in,

[0159] R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0160] a, b and c are each independently an integer from 2 to 20,

[0161] X is selected from the group consisting of F, CI, Br and I.

[0162] In a specific embodiment of the method for preparing lipids 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 (2) can be carried out in a solvent (e.g., dichloromethane (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., dichloromethane (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.

[0163] The third aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-2, comprising the step of reacting the compound of Chemical Formula e obtained in the second aspect of the present invention with the compound of Chemical Formula g:

[0164] [Chemical formula e]

[0165] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0166] [Chemical formula g]

[0167] H2N-(CH2) 1-20 -N(C 1-20 Alkyl)2

[0168] [Chemical formula 1-2]

[0169] (C 1-20 Alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2

[0170] in,

[0171] R' is independently , or

[0172] ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0173] a, b and c are each independently an integer from 2 to 20.

[0174] In a specific embodiment of the method for preparing lipids according to the third aspect of the present invention, the reaction can be carried out in a solvent (eg, n-butanol (n-BuOH)) under reflux, but is not limited thereto.

[0175] The fourth aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-3, comprising the step of reacting the compound of Chemical Formula E obtained in the second aspect of the present invention with the compound of Chemical Formula H:

[0176] [Chemical formula e]

[0177] H2C=CH-C(=O)-HN-(CH2) a -C(=O)OR'

[0178] [Chemical formula h]

[0179] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl)

[0180] [Chemical formula 1-3]

[0181] AN(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A

[0182] in,

[0183] R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group,

[0184] A is -CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R',

[0185] a, b and c are each independently an integer from 2 to 20,

[0186] X is selected from the group consisting of F, CI, Br and I.

[0187] In a specific embodiment of the method for preparing lipids according to the fourth aspect of the present invention, the reaction can be carried out in a solvent (eg, n-butanol (n-BuOH)) under reflux, but is not limited thereto.

[0188] A fifth aspect of the present invention provides a method for preparing a lipid having a structure represented by Chemical Formula 1-4, comprising the following steps: (1) reacting a compound of Chemical Formula a with a compound of Chemical Formula b' to obtain a compound of Chemical Formula c'; (2) reacting a compound of Chemical Formula c' with a compound of Chemical Formula d to obtain a compound of Chemical Formula e'; and (3) reacting a compound of Chemical Formula e' with a compound of Chemical Formula h:

[0189] [Chemical formula a]

[0190] H2N-(CH2) a -C(=O)OH

[0191] [Chemical formula b']

[0192] OH-R2

[0193] [Chemical formula c']

[0194] H2N-R1-C(=O)O-R2

[0195] [Chemical formula d]

[0196]

[0197] [Chemical formula e']

[0198] H2C=CH-C(=O)-HN-R1-C(=O)O-R2

[0199] [Chemical formula h]

[0200] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl)

[0201] [Chemical formula 1-4]

[0202] A'-N(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A'

[0203] in,

[0204] A' is -CH2-CH2-C(=O)-HN-R1-C(=O)O-R2,

[0205] R1 is independently a substituted or unsubstituted saturated or unsaturated divalent hydrocarbon group,

[0206] R2 is independently a substituted or unsubstituted unsaturated monovalent hydrocarbon group,

[0207] a is an integer from 2 to 20,

[0208] X is selected from the group consisting of F, CI, Br and I.

[0209] In a specific embodiment of the lipid preparation method according to the fifth 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 (2) can be carried out in a solvent (e.g., dichloromethane (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) conditions, 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.

[0210] The lipid having a specific structure according to the present invention can easily form a complex with anionic drugs and thus can be used for drug delivery.

[0211] Therefore, according to a sixth aspect of the present invention, a composition for drug delivery comprising the lipid of the present invention is provided.

[0212] In a specific embodiment, the drug can be selected from nucleic acids, polypeptides, viruses or a combination thereof.

[0213] The “nucleic acid” may be, for example, DNA, RNA, siRNA, shRNA, miRNA, mRNA, aptamer, antisense oligonucleotide, or a combination thereof, but is not limited thereto.

[0214] The "polypeptide" may refer to a protein active in vivo, 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 vivo, including a polypeptide sequence of an antigen, an analog thereof or a precursor thereof.

[0215] In one embodiment, the lipids of the present invention can form a complex with a drug, and the complex is encapsulated inside the nanoparticle structure formed by the amphiphilic block copolymer.

[0216] In a specific embodiment, the amphiphilic block copolymer may be an AB type block copolymer comprising a hydrophilic A block and a hydrophobic B block. The AB type block copolymer forms core-shell polymer nanoparticles in an aqueous phase, wherein the hydrophobic B block forms the core (inner wall) and the hydrophilic A block forms the shell (outer wall).

[0217] In a specific embodiment, the hydrophilic A block may be selected from one or more of polyalkylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide and their derivatives.

[0218] More specifically, the hydrophilic A block may be one or more selected from monomethoxypolyethylene glycol (mPEG), monoacetoxypolyethylene glycol, polyethylene glycol, a copolymer of polyethylene and propylene glycol, and polyvinyl pyrrolidone.

[0219] In addition, as needed, by chemically binding the end of the hydrophilic A block to a functional group that can reach a specific tissue or cell, a ligand, or a functional group that can promote intracellular delivery, the in vivo distribution of the nanoparticle carrier can be adjusted or the efficiency of the nanoparticle carrier delivered into the cell can be improved. In a specific embodiment, the functional group or ligand can be selected from one or more of monosaccharides, polysaccharides, vitamins, peptides, proteins, and antibodies against cell surface receptors. More specifically, the functional group or ligand can be selected from one or more of anisamide, vitamin B9 (folic acid), vitamin B12, vitamin A, galactose, lactose, mannose, hyaluronic acid, RGD peptide, NGR peptide, transferrin, antibodies against transferrin receptors, etc.

[0220] The hydrophobic B block is a biocompatible and biodegradable polymer. In a specific embodiment, the hydrophobic B block can be one or more selected from polyester, polyanhydride, polyamino acid, polyorthoester and polyphosphazene.

[0221] More specifically, the hydrophobic B block may be one or more selected from 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.

[0222] Furthermore, in a specific embodiment, the hydrophobic B block can be modified by chemically bonding tocopherol, cholesterol or a fatty acid having 10 to 24 carbon atoms to the hydroxyl group at the end of the hydrophobic B block to increase the hydrophobicity of the hydrophobic B block and improve the stability of the nanoparticles.

[0223] The present invention will be described in more detail below with reference to the following examples. However, the examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto in any way.

[0224] [Example]

[0225] Example 1

[0226] 1-1. Based on Figure 1 The synthetic overview shown below prepares the compound of Formula A.

[0227] [Chemical formula A]

[0228]

[0229] 1-2. Synthesis of 6-acrylamidohexanoate

[0230] 6-aminohexanoic acid (10 g, 76.23 mmol, 1.1 equivalent), undecan-1-ol (11.94 g, 69.30 mmol, 1 equivalent), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 equivalent) and cyclohexane (120 mL) were added to a 250 mL three-neck round bottom flask (RBF), and a Dean-Stark trap and a condenser were installed, followed by stirring and reflux. After 24 hours, the reaction product was concentrated under vacuum, extracted with methylene chloride (MC) and a 3% sodium hydroxide aqueous solution, and then the methylene chloride layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity undecyl 6-aminohexanoate. Without further purification, undecyl 6-aminohexanoate, dichloromethane (100 mL) and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 equivalents) were added to a 250 mL 3-neck RBF. After cooling to 0° C., acryloyl chloride (6.90 g, 76.23 mmol, 1.1 equivalents) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25° C.) and stirred. After 4 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the dichloromethane layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified using a silica gel column with ethyl acetate:hexane (1:1) to obtain 6-acrylamidoundecylhexanoate (17.22 g, yield: 73%).

[0231] 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)

[0232] 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-triazaoctadecan-18-oate

[0233] 6-Acrylamidoundecylhexanoate (3 g, 8.83 mmol, 3 equivalents), tert-butyl(2-aminoethyl)carbamate (0.47 g, 2.94 mmol, 1 equivalent) and n-butanol (n-BuOH) (40 mL) were added to a 100 mL single-necked (1-neck) RBF, followed by stirring and reflux. After 4 days, the mixture was concentrated in vacuo at 70°C and purified using a silica gel column with dichloromethane:methanol:ammonium hydroxide (15:1:0.1) to obtain 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, yield: 54%).

[0234] 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)

[0235] 1-4. Synthesis of the compound of formula A

[0236] In a 100mL single-necked 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-acid (1 g, 1.19 mmol) and dichloromethane (20 mL) were added, and trifluoroacetic acid (TFA) (2 mL) was injected 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 dichloromethane layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain a compound of formula A (0.31 g, 35%).

[0237] 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)

[0238] Example 2

[0239] 2-1. Based on Figure 2 The synthetic overview shown prepares the compound of Formula B below.

[0240] [Chemical formula B]

[0241]

[0242] 2-2. Synthesis of 2-hexyldecyl 6-acrylamidohexanoate

[0243] 6-aminocaproic acid (10 g, 76.23 mmol, 1.1 equivalents), 2-hexyldecane-1-ol (2-hexyldecan-1-ol) (16.80 g, 69.30 mmol, 1 equivalent), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82 g, 83.16 mmol, 1.2 equivalents) and cyclohexane (120 mL) were added to a 250 mL 3-neck RBF, and a Dean Stark separator and condenser were installed, followed by stirring and refluxing. After 24 hours, the mixture was cooled to room temperature and concentrated in vacuo, extracted with dichloromethane and 3% aqueous sodium hydroxide solution, and then the dichloromethane layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-hexyldecyl 6-aminohexanoate. Without further refining, 2-hexyldecyl 6-aminocaproate, dichloromethane (100 mL) and triethylamine (TEA) (15.43 g, 152.46 mmol, 2.2 equivalents) obtained above were added to a 250 mL 3-neck RBF, cooled to 0 ° C, and then acryloyl chloride (6.90 g, 76.23 mmol, 1.1 equivalents) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25 ° C) and stirred. After 4 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the dichloromethane layer was dried with sodium sulfate and filtered. The filtrate was vacuum concentrated and refined with a silica gel column with ethyl acetate: hexane (1: 1) to obtain 2-hexyldecyl-6-acrylamide caproate (14.25 g, yield: 50%).

[0244] 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)

[0245] 2-3. Synthesis of 2-hexyldecyl 8-(3-((6-((2-hexyldecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecan-18-oate

[0246] 2-Hexyldecyl-6-acrylamidohexanoate (4 g, 9.76 mmol, 3 equivalents), (2-aminoethyl)carbamic acid tert-butyl ester (0.52 g, 3.25 mmol, 1 equivalent) and n-butanol (n-BuOH) (40 mL) were added to a 100 mL single-necked RBF, followed by stirring and reflux. After 4 days, the mixture was concentrated in vacuo at 70°C and purified using a silica gel column with dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain 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-acid (2.23 g, yield: 70%).

[0247] 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)

[0248] 2-4. Synthesis of the compound of formula B

[0249] In a 100mL single-necked 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-acid (2g, 2.04mmol) and dichloromethane (40mL) were added, and trifluoroacetic acid (TFA) (4mL) was injected 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 dichloromethane layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain a compound of formula B (1.21g, 67%).

[0250] 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)

[0251] Example 3

[0252] 3-1. Based on Figure 3 The synthetic overview shown prepares the compound of Formula C below.

[0253] [Chemical formula C]

[0254]

[0255] 3-2. Synthesis of the compound of formula C

[0256] 2-Hexyldecyl-6-acrylamide hexanoate (3 g, 7.32 mmol, 3 equivalents), N,N-dimethylethylenediamine (0.22 g, 2.44 mmol, 1 equivalent) and n-butanol (n-BuOH) (30 mL) synthesized in Example 2-2 were added to a 100 mL single-necked RBF, and then stirred and refluxed. After 3 days, vacuum concentration was performed at 70 ° C, and the mixture was refined with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula C (0.95 g, yield: 43%).

[0257] 1H-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)

[0258] Example 4

[0259] 4-1. Based on Figure 4 The synthetic overview shown prepares the compound of Formula D below.

[0260] [Chemical formula D]

[0261]

[0262] 4-2. Synthesis of 2-butyloctyl 6-acrylamidohexanoate

[0263] In 500mL 3-neck RBF, add 6-aminohexanoic acid (6-aminohexanoic acid) (5.03g, 38.32mmol, 1.20 equivalents), 2-butyl-1-n-octanol (5.95g, 31.93mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (10.93g, 57.48mmol, 1.80 equivalents) and cyclohexane (200mL), install Dean Stark separator and condenser, then stir and reflux. After 24 hours, the mixture is cooled to room temperature and vacuum concentrated, extracted with dichloromethane and 3% sodium hydroxide aqueous solution, then dried with sodium sulfate dichloromethane layer and filtered. The filtrate is vacuum concentrated to obtain low-purity 2-butyloctyl-6-aminocaproate. Without further purification, the previously obtained 2-butyloctyl-6-aminocaproate, dichloromethane (170 mL) and triethylamine (7.11 g, 70.28 mmol, 2.20 equivalents) were added to a 250 mL 3-neck RBF, cooled to 0 ° C, and then acryloyl chloride (3.18 g, 35.12 mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25 ° C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, and the organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with ethyl acetate (EtOAc): hexane (1: 2) on a silica gel column to obtain 2-butyloctyl-6-acrylamidecaproate (5.0 g, yield: 44%).

[0264] 1H-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)

[0265] 4-3. Synthesis of the compound of formula D

[0266] 2-Butyloctyl-6-acrylamide hexanoate (1000.00 mg, 2.83 mmol, 2.60 equivalents), N,N'-dimethyl-1,3-propanediamine (111.16 mg, 1.09 mmol, 1.00 equivalents) and n-BuOH (11 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain a compound of formula D (712.60 mg, yield: 81%).

[0267] 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)

[0268] Example 5

[0269] 5-1. Based on Figure 5 The synthetic overview shown prepares the compound of Formula E below.

[0270] [Chemical formula E]

[0271]

[0272] 5-2. Synthesis of 2-hexyloctyl-6-acrylamidohexanoate

[0273] In 500mL 3-neck RBF, add 6-aminocaproic acid (1.84g, 13.99mmol, 1.20 equivalents), 2-hexyl-1-n-octanol (2.50g, 11.66mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (3.99g, 20.99mmol, 1.80 equivalents) and cyclohexane (120mL), install Dean Stark separator and condenser, then stir and reflux. After 24 hours, the mixture is cooled to room temperature, vacuum concentrated, extracted with dichloromethane and 3% sodium hydroxide aqueous solution, then dried with sodium sulfate dichloromethane layer and filtered. The filtrate is vacuum concentrated to obtain low-purity 2-hexyloctyl-6-aminocaproic acid ester. In the absence of further refining, the 2-hexyloctyl-6-aminocaproic acid ester, dichloromethane (60mL), triethylamine (2.60g, 25.65mmol, 2.20 equivalents) and dichloromethane (60mL) obtained above were added to a 250mL 3-neck RBF and cooled to 0°C, and then acryloyl chloride (1.16g, 12.83mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to normal temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with EtOAc: hexane (1:2) to obtain 2-hexyloctyl-6-acrylamide caproic acid ester (3.63g, yield: 82%).

[0274] 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)

[0275] 5-3. Synthesis of the compound of formula E

[0276] 2-Hexyloctyl-6-acrylamide hexanoate (660.27 mg, 1.73 mmol, 2.60 equivalents), N, N'-dimethyl-1,3-propylenediamine (68.00 mg, 0.67 mmol, 1.00 equivalents) and n-BuOH (7 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C, and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain a compound of formula E (375.60 mg, yield: 65%).

[0277] 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)

[0278] Example 6

[0279] 6-1. According to Figure 6 The synthetic overview shown prepares the compound of Formula F below.

[0280] [Chemical formula F]

[0281]

[0282] 6-2. Synthesis of butyl 6-acrylamidohexanoate

[0283] In 500mL 3-neck RBF, add 6-aminocaproic acid (6.37g, 48.57mmol, 1.20 equivalents), butan-1-ol (3.00g, 40.47mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (15.40g, 80.95mmol, 2.00 equivalents) and cyclohexane (200mL), install Dean Stark separator and condenser, then stir and reflux.After 24 hours, the mixture is cooled to normal temperature, vacuum concentrated, extracted with dichloromethane and 3% sodium hydroxide aqueous solution, then dried with sodium sulfate dichloromethane layer and filtered.The filtrate is vacuum concentrated to obtain low-purity 6-aminocaproic acid butyl ester. In the absence of further refining, 6-aminocaproic acid butyl ester, methylene chloride (200mL) and triethylamine (9.01g, 89.04mmol, 2.20 equivalents) obtained above were added in a 500mL 3-neck RBF and cooled to 0°C, then acryloyl chloride (4.03g, 44.52mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to normal temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and refined with a silica gel column with EtOAc: hexane (1:1) to obtain 6-acrylamide butyl hexanoate (3.58g, yield: 37%).

[0284] 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)

[0285] 6-3. Synthesis of the compound of formula F

[0286] 6-Acrylamidohexanoic acid butyl ester (700.00 mg, 2.90 mmol, 2.60 equivalents), N, N'-dimethyl-1,3-propanediamine (113.99 mg, 1.12 mmol, 1.00 equivalents) and n-BuOH (11 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C, and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain a compound of formula F (479.00 mg, yield: 73%).

[0287] 1H-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)

[0288] Example 7

[0289] 7-1. According to Figure 7 The synthetic overview shown prepares the compound of Formula G below.

[0290] [Chemical formula G]

[0291]

[0292] 7-2. Synthesis of 2-octyldodecyl 6-acrylamidohexanoate

[0293] 6-aminocaproic acid (1.05 g, 8.04 mmol, 1.20 equivalents), 2-octyl dodecane-1-ol (2.00 g, 6.70 mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (2.29 g, 12.06 mmol, 1.80 equivalents) and cyclohexane (100 mL) were added to a 250 mL 3-neck RBF, and a Dean Stark separator and condenser were installed, followed by stirring and refluxing. After 24 hours, the mixture was cooled to room temperature, concentrated in vacuo, extracted with dichloromethane and 3% aqueous sodium hydroxide solution, and then the dichloromethane layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-octyl dodecyl-6-aminocaproic acid ester. In the absence of further refining, 2-octyl dodecyl-6-aminocaproic acid ester, dichloromethane (33mL) and triethylamine (1.49g, 14.74mmol, 2.20 equivalents) obtained above were added to a 100mL 3-neck RBF and cooled to 0°C, and then acryloyl chloride (0.67g, 7.37mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with EtOAc: hexane (1:2) to obtain 2-octyl dodecyl-6-acrylamide caproic acid ester (1928.20mg, yield: 62%).

[0294] 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)

[0295] 7-3. Synthesis of the compound of formula G

[0296] 2-Octyldodecyl-6-acrylamide hexanoate (592.57 mg, 1.27 mmol, 2.60 equivalents), N,N'-dimethyl-1,3-propylenediamine (50.00 mg, 0.49 mmol, 1.00 equivalents) and n-BuOH (5 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula G (346.8 mg, yield: 69%).

[0297] 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)

[0298] Example 8

[0299] 8-1. According to Figure 8 The synthetic overview shown below prepares the compound of Formula H.

[0300] [Chemical formula H]

[0301]

[0302] 8-2. Synthesis of 2-hexyloctyl 8-acrylamidooctanoate

[0303] In 250mL 3-neck RBF, add 8-aminocaprylic acid (1.78g, 11.19mmol, 1.20 equivalents), 2-hexyloctan-1-ol (2.00g, 9.33mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (3.19g, 16.79mmol, 1.80 equivalents) and cyclohexane (100mL), install Dean Stark separator and condenser, then stir and reflux. After 24 hours, the mixture is cooled to room temperature, vacuum concentrated, extracted with dichloromethane and 3% sodium hydroxide aqueous solution, then dried with sodium sulfate dichloromethane layer and filtered. The filtrate is vacuum concentrated to obtain low-purity 2-hexyloctyl 8-aminocaprylate. In the absence of further refining, the 2-hexyloctyl 8-aminocaprylate obtained above, dichloromethane (100mL) and triethylamine (2.08g, 20.52mmol, 2.20 equivalents) were added to a 250mL 3-neck RBF and cooled to 0°C, then acryloyl chloride (0.93g, 10.26mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to normal temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and refined with a silica gel column with EtOAc: hexane (1: 1) to obtain 2-hexyloctyl-8-acrylamide caprylate (2838.70mg, yield: 74%).

[0304] 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)

[0305] 8-3. Synthesis of the compound of formula H

[0306] 2-Hexyloctyl-8-acrylamide octanoate (703.42 mg, 0.76 mmol, 2.60 equivalents), N,N'-dimethyl-1,3-propylenediamine (30.00 mg, 0.29 mmol, 1.00 equivalents) and n-BuOH (5 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula H (218.90 mg, yield: 81%).

[0307] 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)

[0308] Example 9

[0309] 9-1. According to Fig. 9 The synthetic overview shown below prepares the compounds of Formula I.

[0310] [Chemical Formula I]

[0311]

[0312] 9-2. Synthesis of 2-decyltetradecyl 6-acrylamidohexanoate

[0313] 6-aminocaproic acid (887.70 mg, 6.77 mmol, 1.20 equivalents), 2-decyltetradecane-1-ol (2.00 g, 5.64 mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (1.93 g, 10.15 mmol, 1.80 equivalents) and cyclohexane (100 mL) were added to a 250 mL 3-neck RBF, and a Dean Stark separator and condenser were installed, followed by stirring and refluxing. After 24 hours, the mixture was cooled to room temperature, concentrated in vacuo, extracted with dichloromethane and 3% aqueous sodium hydroxide solution, and then the dichloromethane layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 2-decyltetradecane 6-aminocaproic acid ester. In the absence of further refining, the 2-decyltetradecyl 6-aminocaproic acid ester, dichloromethane (100mL) and triethylamine (1.26g, 12.41mmol, 2.20 equivalents) obtained above were added to a 250mL 3-neck RBF and cooled to 0°C, and then acryloyl chloride (561.44mg, 6.20mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to normal temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with EtOAc: hexane (1:2) to obtain 2-decyltetradecyl 6-acrylamidocaproic acid ester (1.29g, yield: 44%).

[0314] 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)

[0315] 9-3. Synthesis of Compounds of Formula I

[0316] 2-Decyltetradecyl 6-acrylamidohexanoate (306.44 mg, 0.59 mmol, 2.40 equivalents), N,N'-dimethyl-1,3-propylenediamine (25.00 mg, 0.24 mmol, 1.00 equivalents) and n-BuOH (2.5 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain the compound of Formula I (209.2 mg, yield: 75%).

[0317] 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)

[0318] Example 10

[0319] 10-1. According to Fig.10 The synthetic overview shown prepares the compound of Formula J below.

[0320] [Chemical formula J]

[0321]

[0322] 10-2. Synthesis of the compound of formula J

[0323] 2-Hexyldecyl-6-acrylamide hexanoate (2000.00 mg, 4.88 mmol, 3.00 equivalents), N, N'-dimethyl-1,3-propylenediamine (170.00 mg, 1.63 mmol, 1.00 equivalents) and n-BuOH (20 mL) synthesized in Example 2-2 were added to a 100 mL 3-neck RBF, and then stirred and refluxed. After 24 hours, the mixture was concentrated in vacuo at 80 ° C and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula J (934.00 mg, yield: 62%).

[0324] 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)

[0325] Embodiment 11

[0326] 11-1. According to Fig.11 The synthetic overview shown prepares the compound of Formula K below.

[0327] [Chemical formula K]

[0328]

[0329] 11-2. Synthesis of nonyl 6-acrylamidohexanoate

[0330] In 250mL 3 neck RBF, add 6-aminocaproic acid (10g, 76.23mmol, 1.1 equivalents), nonyl-1-alcohol (21.58g, 69.30mmol, 1 equivalent), p-toluenesulfonic acid monohydrate (p-TsOH) (15.82g, 83.16mmol, 1.2 equivalents) and cyclohexane (120mL), install Dean Stark separator and condenser, then stir and reflux.After 24 hours, the mixture is concentrated in vacuo, extracted with dichloromethane and 3% sodium hydroxide aqueous solution, then dried with sodium sulfate dichloromethane layer and filtered.The filtrate is concentrated in vacuo to obtain low-purity 6-aminocaproic acid nonyl ester. In the absence of further refining, the 6-aminohexanoic acid nonyl ester, dichloromethane (100mL) and triethylamine (15.43g, 152.46mmol, 2.2 equivalents) obtained above were added to a 250mL 3-neck RBF and cooled to 0°C, and then acryloyl chloride (6.90g, 76.23mmol, 1.1 equivalents) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25°C) and stirred. After 4 hours, the mixture in the reactor was extracted with a saturated aqueous solution of sodium bicarbonate, and the dichloromethane layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with EtOAc: hexane (1:1) to obtain 6-acrylamide hexanoic acid nonyl ester (15.66g, yield: 66%).

[0331] 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)

[0332] 11-3. Synthesis of the compound of formula K

[0333] 6-Acrylamidohexanoic acid nonyl ester (1000.00 mg, 3.21 mmol, 2.60 equivalents), N,N'-dimethyl-1,3-propanediamine (126.18 mg, 1.23 mmol, 1.00 equivalents) and n-BuOH (10 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain a compound of formula K (770.10 mg, yield: 86%).

[0334] 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)

[0335] Example 12

[0336] 12-1. According to Fig.12 The synthetic overview shown prepares the compound of Formula L below.

[0337] [Chemical formula L]

[0338]

[0339] 12-2. Synthesis of the compound of formula L

[0340] In a 100 mL 3-neck RBF, 2-butyloctyl-6-acrylamide hexanoate (850.65 mg, 2.43 mmol, 2.60 equiv.) synthesized in Example 4-2, tert-butyl N-(2-aminoethyl)carbamate (150.00 mg, 0.94 mmol, 1.00 equiv.) and n-BuOH (10 mL) were added, followed by stirring and reflux. After 48 hours, the mixture was concentrated in vacuo at 80°C and purified by silica gel column with dichloromethane:methanol:ammonium hydroxide (15:1:0.1) to obtain low-purity 2-butyloctyl 8-(3-((6-((2-butyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecan-18-oate. Then, the synthesis of the compound of Chemical Formula L was carried out without further purification process. In a 25mL single-necked RBF, 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-acid (143.20mg, 0.16mmol) and dichloromethane (2mL) were added, and trifluoroacetic acid (0.2mL) was injected 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 with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain a compound of formula L (85.1mg, 67%).

[0341] 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)

[0342] Embodiment 13

[0343] 13-1. According to Fig.13 The synthetic overview shown prepares the compound of Formula M below.

[0344] [Chemical formula M]

[0345]

[0346] 13-2. Synthesis of the compound of formula M

[0347] In a 100 mL 3-neck RBF, 2-hexyloctyl-6-acrylamide hexanoate (1429.07 mg, 3.74 mmol, 2.40 equiv) synthesized in Example 5-2, tert-butyl N-(2-aminoethyl)carbamate (250.00 mg, 1.56 mmol, 1.00 equiv) and n-BuOH (10 mL) were added, followed by stirring and reflux. After 48 hours, the mixture was concentrated in vacuo at 80°C and purified by silica gel column with dichloromethane:methanol:ammonium hydroxide (15:1:0.1) to obtain low-purity 2-hexyloctyl ester 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecan-18-oate. Then, the synthesis of the compound of Chemical Formula M was carried out without further purification process. 2-Hexyloctyl ester 8-(3-((6-((2-hexyloctyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecane-18-acid ester and dichloromethane (3 mL) were added to a 25 mL single-necked 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 with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (8: 1: 0.1) to obtain the compound of formula M (116.6 mg, 9.1% for two steps).

[0348] 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)

[0349] Embodiment 14

[0350] 14-1. According to Fig.14 The synthetic overview shown prepares the compound of Formula N below.

[0351] [Chemical formula N]

[0352]

[0353] 14-2. Synthesis of the compound of formula N

[0354] In a 100 mL 3-neck RBF, 2-octyldodecyl-6-acrylamide hexanoate (1200.00 mg, 2.58 mmol, 2.40 equiv) synthesized in Example 7-2, tert-butyl N-(2-aminoethyl)carbamate (171.99 mg, 1.07 mmol, 1.00 equiv) and n-BuOH (10 mL) were added, followed by stirring and reflux. After 48 hours, the mixture was concentrated in vacuo at 80°C and purified by silica gel column with dichloromethane:methanol:ammonium hydroxide (15:1:0.1) to obtain low-purity 2-octyldodecyl-2,2-dimethyl-8-(3-((6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-4,11-dioxo-3-oxa-5,8,12-triazaoctadecan-18-oate. Then, the synthesis of the compound of Chemical Formula N was carried out without further purification process. 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-acid and dichloromethane (10 mL) were added to a 100 mL single-necked 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 with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain the compound of formula N (137.8 mg, 12.9% for two steps).

[0355] 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)

[0356] Embodiment 15

[0357] 15-1. According to Fig.15 The synthetic overview shown prepares the compound of Formula O below.

[0358] [Chemical formula O]

[0359]

[0360] 15-2. Synthesis of the compound of formula O

[0361] 2-Hexyloctyl-8-acrylamide caprylate (1130.14 mg, 2.76 mmol, 2.60 equiv.) synthesized in Example 8-2, tert-butyl N-(2-aminoethyl)carbamate (170.00 mg, 1.06 mmol, 1.00 equiv.) and n-BuOH (11 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 48 hours, the mixture was concentrated in vacuo at 80°C and purified by silica gel column with dichloromethane:methanol:ammonium hydroxide (15:1:0.1) to obtain low-purity 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. Then, the synthesis of the compound of formula O was carried out without further purification process. 2-Hexyloctyl ester 8-(3-((8-((2-hexyloctyl)oxy)-8-oxooctyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaeicosane-20-acid ester and dichloromethane (4.4 mL) were added to a 25 mL single-necked 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 with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain the compound of formula O (225.5 mg, 24.2% in two steps).

[0362] 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)

[0363] Example 16

[0364] 16-1. According to Fig.16 The synthetic overview shown prepares the compound of Formula P below.

[0365] [Chemical formula P]

[0366]

[0367] 16-2. Synthesis of the compound of formula P

[0368] In a 100 mL 3-neck RBF, 2-decyltetradecyl 6-acrylamidohexanoate (891.15 mg, 1.71 mmol, 2.40 equiv) synthesized in Example 9-2, tert-butyl N-(2-aminoethyl)carbamate (114.00 mg, 0.71 mmol, 1.00 equiv) and n-BuOH (6.2 mL) were added, followed by stirring and reflux. After 48 hours, the mixture was concentrated in vacuo at 80°C and purified by silica gel column with dichloromethane:methanol:ammonium hydroxide (20:1:0.1) to obtain low-purity 2-decyltetradecyl 8-(3-((6-((2-decyltetradecyl)oxy)-6-oxohexyl)amino)-3-oxopropyl)-2,2-dimethyl-4,11-dioxo-3-oxa-5,8,12-triazaoctadecan-18-oate. Then, the synthesis of the compound of formula P was carried out without further purification process. 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-acid ester and dichloromethane (6.0 mL) were added to a 25 mL single-necked RBF, 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 with sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain a compound of formula P (157.9 mg, 20.1% in two steps).

[0369] 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)

[0370] Embodiment 17

[0371] 17-1. According to Fig.17 The synthetic overview shown prepares the compound of Formula Q below.

[0372] [Chemical formula Q]

[0373]

[0374] 17-2. Synthesis of the compound of formula Q

[0375] 6-Acrylamide hexanoic acid nonyl ester (3000.00 mg, 9.63 mmol, 2.60 equivalents), N, N-dimethylpropylenediamine (378.53 mg, 1.00 mmol, 1.00 equivalents) and n-BuOH (18 mL) synthesized in Example 11-2 were added to a 100 mL 3-neck RBF, and then stirred and refluxed. After 24 hours, the mixture was concentrated in vacuo at 80 ° C and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (7: 1: 0.1) to obtain a compound of formula Q (1257.6 mg, yield: 47%).

[0376] 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)

[0377] Embodiment 18

[0378] 18-1. According to Fig.18 The synthetic overview shown prepares the compound of Formula R below.

[0379] [Chemical formula R]

[0380]

[0381] 18-2. Synthesis of the compound of formula R

[0382] 2-Hexyldecyl-6-acrylamide hexanoate (1500.00 mg, 3.67 mmol, 2.60 equivalents), N,N-dimethylpropylenediamine (143.90 mg, 1.41 mmol, 1.00 equivalents) and n-BuOH (7 mL) synthesized in Example 2-2 were added to a 100 mL 3-neck RBF, and then stirred and refluxed. After 24 hours, the mixture was concentrated in vacuo at 80 ° C and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula R (476.10 mg, yield: 37%).

[0383] 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)

[0384] Embodiment 19

[0385] 19-1. According to Fig.19 The synthetic overview shown prepares the compound of Formula S below.

[0386] [Chemical formula S]

[0387]

[0388] 19-2. Synthesis of the compound of formula S

[0389] 2-Hexyldecyl-6-acrylamide hexanoate (2000.00 mg, 4.88 mmol, 3.00 equivalents), 2-morpholinoethan-1-ol (210.00 mg, 1.63 mmol, 1.00 equivalents) and n-BuOH (20 mL) synthesized in Example 2-2 were added to a 100 mL 3-neck RBF, and then stirred and refluxed. After 48 hours, the mixture was concentrated in vacuo at 80 ° C and refined with a silica gel column with dichloromethane: methanol: ammonium hydroxide (15: 1: 0.1) to obtain a compound of formula S (596.00 mg, yield: 39%).

[0390] 1H-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)

[0391] Embodiment 20

[0392] 20-1. According to Fig. 20 The synthetic overview shown prepares the compound of Formula T below.

[0393] [Chemical formula T]

[0394]

[0395] 20-2. Synthesis of dec-3-yn-1-yl 6-acrylamidohexanoate

[0396] 6-aminohexanoic acid (3.06 g, 23.34 mmol, 1.20 equivalents), 3-decyne-1-ol (dec-3-yn-1-ol) (3.00 g, 19.45 mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (5.55 g, 29.17 mmol, 1.50 equivalents) and cyclohexane (130 mL) were added to a 500 mL 3-neck RBF, and a Dean Stark separator and a condenser were installed, followed by stirring and reflux. After 24 hours, the mixture was cooled to room temperature, concentrated in vacuo, extracted with dichloromethane and an aqueous NaOH solution, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity 6-aminohexanoic acid 3-decyne-1-ester (dec-3-yn-1-yl 6-aminohexanoate). In the absence of further refining, 6-aminocaproic acid 3-decyne-1-ester, dichloromethane (130mL) and triethylamine (4.33g, 42.79mmol, 2.20 equivalents) obtained above were added to a 500mL 3-neck RBF and cooled to 0°C, then acryloyl chloride (1.94g, 21.39mmol, 1.10 equivalents) was injected dropwise. The temperature of the reactor was raised to normal temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and refined with a silica gel column with EtOAc: hexane (1:2) to obtain 6-acrylamidecaproic acid 3-decyne-1-ester (765.60mg, yield: 12%).

[0397] 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)

[0398] 20-3. Synthesis of the compound of formula T

[0399] 6-Acrylamidohexanoic acid 3-decyne-1-ester (300.00 mg, 0.94 mmol, 2.20 equivalents), N,N'-dimethyl-1,3-propanediamine (43.80 mg, 0.43 mmol, 1.00 equivalents) and n-BuOH (5 mL) were added to a 100 mL 3-neck RBF, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula T (165.3 mg, yield: 52%).

[0400] 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)

[0401] Embodiment 21

[0402] 21-1. According to Fig.21 The synthetic overview shown prepares the compound of Formula U below.

[0403] [Chemical formula U]

[0404]

[0405] 21-2. Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl 6-acrylamidohexanoate

[0406] 6-aminocaproic acid (295.37 mg, 2.25 mmol, 1.20 equivalents), (9Z, 12Z)-octadeca-9,12-dien-1-ol (500.00 mg, 1.88 mmol, 1.00 equivalents), p-toluenesulfonic acid monohydrate (642.47 mg, 3.38 mmol, 1.80 equivalents) and cyclohexane (20 mL) were added to a 100 mL 3-neck RBF, and a Dean Stark separator and a condenser were installed, followed by stirring and reflux. After 24 hours, the mixture was cooled to room temperature, concentrated in vacuo, extracted with dichloromethane and a NaOH aqueous solution, and the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain low-purity (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, dichloromethane (20 mL) and triethylamine (417.72 mg, 4.13 mmol, 2.20 equiv) were added to a 100 mL 3-neck RBF and cooled to 0°C, and then acryloyl chloride (186.82 mg, 2.06 mmol, 1.10 equiv) was injected dropwise. The temperature of the reactor was raised to room temperature (20-25°C) and stirred. After 18 hours, the mixture in the reactor was extracted with HCl aqueous solution, and the organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified using a silica gel column with EtOAc:hexane (1:2) to obtain (9Z,12Z)-octadec-9,12-dien-1-yl 6-acrylamide hexanoate (579.9 g, yield: 71%).

[0407] 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)

[0408] 21-3. Synthesis of the compound of formula U

[0409] In a 100 mL 3-neck RBF, (9Z, 12Z)-octadec-9,12-diene-1-yl 6-acrylamide hexanoate (305.258 mg, 0.70 mmol, 2.40 equivalents), N,N'-dimethyl-1,3-propanediamine (30.00 mg, 0.29 mmol, 1.00 equivalents) and n-BuOH (3 mL) were added, followed by stirring and reflux. After 24 hours, the mixture was concentrated in vacuo at 80 ° C. and purified with a silica gel column using dichloromethane: methanol: ammonium hydroxide (10: 1: 0.1) to obtain a compound of formula U (185.10 mg, yield: 65%).

[0410] 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)

[0411] Embodiment 22

[0412] 22-1. According to Fig. 22 The synthetic overview shown below prepares the compound of Formula V.

[0413] [Chemical Formula V]

[0414]

[0415] 22-2. Synthesis of 1-cyclopropylnonyl 6-(((benzyloxy)carbonyl)amino)hexanoate

[0416] In a 500 mL 3-neck RBF, 1-cyclopropylnonan-1-ol (8.68 g, 47.1 mmol, 1.00 equiv) and dichloromethane (170 mL) were added at 25°C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (11.7 g, 61.3 mmol, 1.30 equiv) and triethylamine (Et3N) (9.54 g, 94.2 mmol, 2.00 equiv) were added to the mixture. 6-(((benzyloxy)carbonyl)amino)hexanoic acid (15.0 g, 56.5 mmol, 1.20 equiv) and 4-dimethylaminopyridine (DMAP) (1.15 g, 9.42 mmol, 0.20 equiv) were added. The mixture is purged with nitrogen (N2) 3 times.The mixture is stirred at 25 ° C for 16 hours.The reaction mixture is diluted with water (200mL), and extracted with dichloromethane 600mL (200mL×3).The dichloromethane layer is collected, dried using sodium sulfate, then filtered and the filtrate is concentrated under reduced pressure to obtain residue.Residue is refined with column chromatography (SiO2, petroleum ether (PE) / ethyl acetate (EtOAc)=10 / 1 to 1 / 100).1-cyclopropylnonyl-6-(((benzyloxy)carbonyl)amino)hexanoate (9.00g, 20.9mmol, 44.3% yield) is obtained as a colorless oil.

[0417] 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)

[0418] 22-3. Synthesis of 1-cyclopropylnonyl 6-aminohexanoate

[0419] Palladium catalyst (Pd / C) (2.22 g, 2.09 mmol, 10% purity, 0.10 equiv.) was added to a 35 mL portion of a cylindrical flask under an argon (Ar) atmosphere. Tetrahydrofuran (THF) (90 mL) was added to the upper portion of the cylindrical flask. 1-cyclopropylnonyl-6-(((benzyloxy)carbonyl)amino)hexanoate (9.00 g, 20.9 mmol, 1.00 equiv.) was added to the mixture. Hydrogen (H2) was filled to 50 pounds per square inch (psi). The mixture was stirred at 50 ° C for 16 hours. The Pd / C filter cake was safely filtered and collected. The filtrate was concentrated under pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 10 / 1 to 1 / 100) to obtain 1-cyclopropyl 6-aminohexanoic acid nonyl ester (6.00 g, 20.2 mmol, yield: 96.7%) as a yellow oil.

[0420] 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)

[0421] 22-4. Synthesis of 1-cyclopropylnonyl6-acrylamidohexanoate

[0422] Dichloromethane (30mL) and 1-cyclopropyl 6-aminohexanoic acid nonyl ester (3.00g, 10.1mmol, 1.00 equivalent) were added to a 100mL 3-neck RBF. Triethylamine (TEA) (4.59g, 45.4mmol, 4.50 equivalents) was added to the mixture at 0°C. Acryloyl chloride (1.37g, 15.1mmol, 1.50 equivalents) was added dropwise to the mixture at 0°C. The mixture was stirred at 0°C for 2 hours and then slowly returned to room temperature. Water (40mL) was added at 20°C to neutralize the reaction mixture, which was then extracted with dichloromethane (50mL×3). The combined organic layer was dried over sodium sulfate, then filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was refined with column chromatography (SiO2, PE / EtOAc=10 / 1 to 1 / 100). 1-Cyclopropyl 6-acrylamidohexanoic acid nonyl ester (2.60 g, 7.40 mmol, 73.3% yield) was obtained as a yellow oil.

[0423] 1 H NMR (400 MHz, CDCl3) δ 6.34 - 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)

[0424] 22-5. Synthesis of the compound of formula V

[0425] A mixed solution of dimethyl sulfoxide (DMSO) (3.5 mL) and water (3.5 mL) and 1-cyclopropyl 6-acrylamidohexanoate (0.70 g, 1.99 mmol, 1.00 eq.) were added to a 50 mL 3-necked RBF. TEA (134 mg, 1.33 mmol, 0.67 eq.) was added to the mixture. N 1 ,N 3 -Dimethylpropane-1,3-diamine (N 1 ,N 3-dimethylpropane-1,3-diamine)(67.8mg, 663μmol, 0.33 equivalent). The mixture was purged with N2 3 times. The mixture was stirred at 100 ° C for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was refined by column chromatography (SiO2, dichloromethane / methanol=10 / 1) to obtain 0.3g of a relatively low-purity compound of formula V. It was refined by reverse phase HPLC (column: Phenomenex luna C18 15025mm 10μm; mobile phase: [water (FA)-ACN]; slope: 40%-70%B, for 10 minutes) to obtain a compound of formula V (0.15g, 186μmol, 28.1% yield, 96.1% purity) in the form of a yellow oil.

[0426] 1 H NMR (400 MHz, CDCl3) δ 7.91 (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)

[0427] [Preparation Example of Composition for Drug Delivery]

[0428] 1. Preparation of raw materials

[0429] As shown in the table below, the substances required for preparing the preparations were dissolved in each dilution solvent to prepare the desired concentrations. When dissolving, the substances were first kept at room temperature, and then the solvent was added to dissolve them.

[0430]

[0431] 2. Mixing of raw materials

[0432] To meet the following ratio, the required amount of raw materials was mixed: N / P ratio (amine group of lipid: phosphate group of mRNA) was 10, each compound of chemical formula A to chemical formula V: DMG-PEG: DSPC: cholesterol = 50: 1.5: 10: 38.5. Ethanol was added to the ethanol layer so that the sum of all raw materials was within 12.5 mM, and the aqueous phase and the ethanol phase were kept at a volume ratio of 3: 1 and mixed. After mixing, in order to reduce the total content of ethanol, buffer exchange was performed as follows: the mixed solution was concentrated to 1 / 3 by centrifugation at 4000 rpm using an Amicon-Ultra tube filter (Merk Millipore, UFC505096 or UFC805024, pore size: 50K, volume: 0.5 mL or 4 mL), and then diluted with PBS 3 times the volume of the concentrate and centrifuged and concentrated. This process was repeated 6 times for buffer exchange.

[0433] The specific process procedures are as follows.

[0434] 1) Prepare two autoclaved tubes (Tube (A), Tube (B)).

[0435] 2) Add the compounds of Formulae A to V, DSPC, cholesterol and DMG-PEG in the molar numbers calculated according to the experimental conditions to tube (A) in sequence, and vortex to mix after addition.

[0436] 3) If necessary, add ethanol to the ethanol phase to bring the sum of all starting materials to within 12.5 mM.

[0437] 4) In tube (B), mRNA and 20mM sodium acetate buffer (pH4.6) (= prepared by diluting 3M sodium acetate buffer to 20mM and titrating to pH 4.6 with 1M HCl) were mixed. At this time, the ratio was calculated so that the volume of the aqueous phase was a total of 3 times the volume of the ethanol phase and added.

[0438] 5) The mixing of tube (A) and tube (B) was performed using a microfluidics (Ignite, Precision Nanosystem) device. The microfluidics operating conditions were a flow rate ratio (FRR) of C:R = 3:1 and a total flow rate (TRR) of 12 mL / min.

[0439] 6) The resultant mixed solution of step 5) was concentrated to 1 / 3 by centrifugation at 4000 rpm using an Amicon-Ultra tube filter (50K), and then diluted 3 times with PBS and concentrated by centrifugation. This process was repeated 6 times to concentrate to the desired volume.

[0440] 3. Evaluation of the physical properties of the preparation

[0441] 1) For the prepared preparation, the particle characteristics (ie, zeta-average particle size (Zeta-average), polydispersity (PDI) and zeta-potential (Zeta-potential)) were confirmed by a particle size analyzer (Dynamic Light Scattering, DLS), and the results are shown in Table 1 below.

[0442] 2) The mRNA encapsulation efficiency of the prepared preparations was confirmed by Ribo-green assay, and the results are shown in Table 1 below.

[0443] [Table 1]

[0444]

Claims

1. A lipid having a structure selected from the following, or an ionized form thereof: as well as in, In the above structures, at least two of the R groups are Rx, and the remaining R groups are Ry, wherein Rx are each independently selected from , , and , 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, R2 is a substituted or unsubstituted unsaturated monovalent hydrocarbon group, represents a substituted or unsubstituted methylene group, Ry is each independently H or a substituted or unsubstituted alkyl group, wherein two Ry groups other than H may be linked together with the nitrogen atom to which they are attached to form a ring structure, L is each independently a substituted or unsubstituted alkylene group, and may optionally have an ether bond (—O—), a thioether bond (—S—), or a disulfide bond (—SS—) in its structure.

2. The lipid according to claim 1, wherein Rx are each independently selected from , , and , wherein a, b and c are each independently an integer of 2 to 20, and R1 is a substituted or unsubstituted saturated or unsaturated divalent C 1-12 Hydrocarbyl, R2 is a substituted or unsubstituted unsaturated monovalent C 2-24 Hydrocarbon, represents a substituted or unsubstituted methylene group, Ry are each independently H or C 1-20 Alkyl, wherein the alkyl groups are each independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-20 In a heterocyclic group, two Ry groups other than H may be joined together with the nitrogen atom to which they are attached to form a ring structure. L is each independently C 1-20 Alkylene, each of which is independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-20 More than one substitution in the heterocyclic group.

3. The lipid according to claim 2, wherein Rx are each independently selected from , , and , wherein a, b and c are each independently an integer of 2 to 15, and R1 is a substituted or unsubstituted saturated or unsaturated divalent C 1-12 Hydrocarbyl, R2 is a substituted or unsubstituted unsaturated monovalent C 2-24 Hydrocarbon, represents a substituted or unsubstituted methylene group, Ry are each independently H or C 1-10 Alkyl, wherein the alkyl groups are each independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-10 In a heterocyclic group, two Ry groups other than H may be joined together with the nitrogen atom to which they are attached to form a ring structure. L is each independently C 1-10 Alkylene, each of which is independently unsubstituted or selected from -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 The carbocyclyl and optionally substituted C 3-10 More than one substitution in the heterocyclic group.

4. The lipid according to claim 3, wherein Rx are each independently selected from , and , wherein a, b and c are each independently an integer from 3 to 12, and R1 is a substituted or unsubstituted C 1-12 Alkylene, substituted or unsubstituted C 2-12 Alkenylene or substituted or unsubstituted C 2-12 Alkyne, R2 is substituted or unsubstituted C 2-24 Alkenyl or substituted or unsubstituted C 2-24 Alkynyl, represents a substituted or unsubstituted methylene group, Ry are each independently H or C 1-6 Alkyl, wherein the alkyl groups are each independently unsubstituted or substituted by one or more selected from -OH and -NH2, and two Ry groups other than H may be linked together with the nitrogen atoms to which they are attached to form a ring structure, L is each independently unsubstituted C 1-6 Alkylene.

5. The lipid according to claim 4, wherein The lipid has any one structure selected from the following Chemical Formulas A to V: 。 6. A method for preparing a lipid having a structure represented by Chemical Formula 1-1, comprising the following steps: (1) reacting a compound of chemical formula a with a compound of chemical formula b to obtain a compound of chemical formula c; (2) reacting the compound of chemical formula c with the compound of chemical formula d to obtain the compound of chemical formula e; as well as (3) reacting the compound of chemical formula e with the compound of chemical formula f, and deprotecting the reaction product, in, [Chemical formula a] H2N-(CH2) a -C(=O)OH [Chemical formula b] OH-R' [Chemical formula c] H2N-(CH2) a -C(=O)O-R' [Chemical formula d] [Chemical formula e] H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' [Chemical formula f] H2N-(CH2) 1-20 -NH-C(=O)OC(CH3)3 [Chemical formula 1-1] H2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2 in, R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, 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, CI, Br and I.

7. A method for preparing a lipid having a structure represented by Chemical Formula 1-2, comprising the step of reacting the compound of Chemical Formula e obtained in claim 6 with the compound of Chemical Formula g: [Chemical formula e] H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' [Chemical formula g] H2N-(CH2) 1-20 -N(C 1-20 Alkyl)2 [Chemical formula 1-2] (C 1-20 Alkyl)2N-(CH2) 1-20 -N[-CH2-CH2-C(=O)-HN-(CH2) a -C(=O)O-R']2 in, R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group, a, b and c are each independently an integer from 2 to 20.

8. A method for preparing a lipid having a structure represented by Chemical Formula 1-3, comprising the step of reacting the compound of Chemical Formula E obtained in claim 6 with the compound of Chemical Formula H, in, [Chemical formula e] H2C=CH-C(=O)-HN-(CH2) a -C(=O)O-R' [Chemical formula h] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl) [Chemical formula 1-3] AN(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A in, R' is independently , or ,in represents the point of attachment to the adjacent oxygen atom, represents a substituted or unsubstituted methylene group, A is -CH2-CH2-C(=O)-HN-(CH2) 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, CI, Br and I.

9. A method for preparing a lipid having a structure represented by Chemical Formula 1-4, 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 the compound of formula d to obtain the compound of formula e'; as well as (3) reacting the compound of formula e' with the compound of formula h, in, [Chemical formula a] H2N-(CH2) a -C(=O)OH [Chemical formula b'] OH-R2 [Chemical formula c'] H2N-R1-C(=O)O-R2 [Chemical formula d] [Chemical formula e'] H2C=CH-C(=O)-HN-R1-C(=O)O-R2 [Chemical formula h] (C 1-10 Alkyl)-NH-(CH2) 1-20 -NH-(C 1-10 alkyl) [Chemical formula 1-4] A'-N(C 1-10 Alkyl)-(CH2) 1-20 -N(C 1-10 Alkyl)-A' in, 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 from 2 to 20, X is selected from the group consisting of F, CI, Br and I. 10 . A composition for drug delivery, comprising the lipid according to claim 1 .

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